DETAILED ACTION
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 .
Election/Restriction
The response filed on 2/2/26 to the restriction requirement of 12/3/25 has been received. Without traverse, Applicant has elected SEQ ID NOs: 1-3 and 84 for “species I” and SEQ ID NOs: 1-6, 13-15, 20, 23, and 84 for “species II”.
Claims 1, 6, 11-13, 44-46, 50-52, 88, 90, 93-95, 97, 102, 103, and 105 are pending and currently under consideration.
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, 6, 11-13, 45, 46, 51, 52, 88, 90, 93-95, 97, 102, 103, and 105 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. In the instant case, the claims are inclusive of: (i) a genus of antibody or antigen-binding fragments thereof that bind to cMET comprising a heavy-chain variable domains (VHH) comprising CDR sequences with as little as 80% identity to each of SEQ ID NOs: 1-3; (ii) a genus of antibody or antigen-binding fragments thereof that bind to cMET comprising a VHH comprising CDR sequences with as little as 80% identity to each of SEQ ID NOs: 4-6; (iii) a genus of antibody or antigen-binding fragments thereof that bind to cMET comprising a VHH comprising CDR sequences with as little as 80% identity to each of SEQ ID NOs: 7-9; (iv) a genus of antibody or antigen-binding fragments thereof that bind to cMET comprising a VHH comprising CDR sequences with as little as 80% identity to each of SEQ ID NOs: 10-12; (v) a genus of antibody or antigen-binding fragments thereof that bind to cMET comprising a VHH comprising a sequence with as little as 80% identity to a sequence selected from SEQ ID NOs: 19-22 and 77-84; (vi) a genus of combinations of VH1 and VL1 that associate with each other to bind EGFR wherein the VH1 comprises CDR sequences with as little as 80% identity to each of SEQ ID NOs: 13-15 and the VL1 comprises CDR sequences with as little as 80% sequence identity to each of SEQ ID NOs:16-18; (vii) a genus of combinations of VH2 and VL2 that associate with each other to bind EGFR wherein the VH2 comprises CDR sequences with as little as 80% identity to each of SEQ ID NOs: 13-15 and the VL2 comprises CDR sequences with as little as 80% sequence identity to each of SEQ ID NOs:16-18; (viii) a genus of combinations first, second, third, and fourth polypeptides of claim 52 that bind EGFR and cMET wherein the first polypeptide comprises a sequence with as little as 80% sequence identity to SEQ ID NO: 64 or 65, the second polypeptide comprises a sequence with as little as 80% sequence identity to SEQ ID NO: 68, the third polypeptide comprises a sequence with as little as 80% sequence identity to SEQ ID NO: 66 or 67, and the fourth polypeptide comprises a sequence with as little as 80% sequence identity to SEQ ID NO: 68; and (ix) a genus of combinations first, second, third, and fourth polypeptides of claim 52 that bind EGFR and cMET wherein the first polypeptide comprises a sequence with as little as 80% sequence identity to SEQ ID NO: 85, the second polypeptide comprises a sequence with as little as 80% sequence identity to SEQ ID NO: 68, the third polypeptide comprises a sequence with as little as 80% sequence identity to SEQ ID NO: 86, and the fourth polypeptide comprises a sequence with as little as 80% sequence identity to SEQ ID NO: 68. However, the written description in this case only sets forth the following members of the genera:
(i) antibody or antigen-binding fragments thereof that bind to cMET comprising a heavy-chain variable domains (VHH) comprising CDR sequences comprising each of SEQ ID NOs: 1-3; (ii) antibody or antigen-binding fragments thereof that bind to cMET comprising a VHH comprising CDR sequences comprising each of SEQ ID NOs: 4-6; (iii) antibody or antigen-binding fragments thereof that bind to cMET comprising a VHH comprising CDR sequences comprising each of SEQ ID NOs: 7-9; (iv) antibody or antigen-binding fragments thereof that bind to cMET comprising a VHH comprising CDR sequences comprising each of SEQ ID NOs: 10-12; (v) antibody or antigen-binding fragments thereof that bind to cMET comprising a VHH comprising a sequence selected from SEQ ID NOs: 19-22 and 77-84; (vi) combinations of VH1 and VL1 that associate with each other to bind EGFR wherein the VH1 comprises CDR sequences comprising each of SEQ ID NOs: 13-15 and the VL1 comprises CDR sequences comprising each of SEQ ID NOs:16-18; (vii) combinations of VH2 and VL2 that associate with each other to bind EGFR wherein the VH2 comprises CDR sequences comprising each of SEQ ID NOs: 13-15 and the VL2 comprises CDR sequences comprising each of SEQ ID NOs:16-18; (viii) combinations first, second, third, and fourth polypeptides of claim 52 that bind EGFR and cMET wherein the first polypeptide comprises a sequence comprising SEQ ID NO: 64 or 65, the second polypeptide comprises a sequence comprising SEQ ID NO: 68, the third polypeptide comprises a sequence comprising SEQ ID NO: 66 or 67, and the fourth polypeptide comprises a sequence with comprising SEQ ID NO: 68; and (ix) combinations first, second, third, and fourth polypeptides of claim 52 that bind EGFR and cMET wherein the first polypeptide comprises a sequence comprising SEQ ID NO: 85, the second polypeptide comprises a sequence comprising SEQ ID NO: 68, the third polypeptide comprises a sequence comprising SEQ ID NO: 86, and the fourth polypeptide comprises a sequence comprising SEQ ID NO: 68. The specification does not disclose, and the art does not teach, the genera as broadly encompassed in the claims.
The specification acknowledges members of the genera are antibody domains that recognize/bind epitopes of antigens (such as cMET and EGFR) via their CDR regions (see line 26 on page 64 to line 18 on page 65, in particular). Further, one of ordinary skill in the art would recognize that the specificity of an antibody is dependent upon the CDR regions within variable domains of the antibody and different combinations of CDR sequences greatly alter antigen binding. Even minor changes in the amino acid sequences of variable domains, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proceedings of the National Academy of Sciences, 1982, 79:1979-1983). 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 function.
MacCallum et al. (Journal of Molecular Biology, 1996, 262:732-745) analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominates, a number of residues outside the standard CDR definitions make antigen contacts (see page 733, right column) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left column).
The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site is underscored by Casset et al. (Biochemical and Biophysical Research Communications, 2003, 307:198-205), which constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs (see entire document). Casset et al. also states that although CDR H3 is at the center of most if not all antigen interactions, other CDRs play an important role in the recognition process (page 199, left column) and this is demonstrated in this work by using all CDRs except CDR L2 and additionally using a framework residue located just before the CDR H3 (see page 202, left column).
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or by describing structural features common to that genus that “constitute a substantial portion of the genus.” See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997): “A description of a genus of cDNAs may be achieved by means of a recitation of a representative number of cDNA, defined by nucleotide sequence, falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus.”
The inventions at issue in Lilly were DNA constructs per se, the holdings of that case is also applicable to claims such as those at issue here. Further, disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product. See Ariad, 598 F.3d at 1354-55 (“Regardless whether the asserted claims recite a compound, Ariad still must describe some way of performing the claimed methods... the specification must demonstrate that Ariad possessed the claimed methods by sufficiently disclosing molecules capable of reducing NF-kB activity so as to ‘satisfy the inventor’s obligation to disclose the technologic knowledge upon which the patent is based, and to demonstrate that the patentee was in possession of the invention that is claimed.’”) (internal citation omitted); see also Univ. of Rochester v. G.D. Searle& Co., Inc., 358 F.3d916,918 (Fed.Cir.2004) (applying the same analysis to assess written description for claims to a “method for selectively inhibiting” a particular enzyme by administering a functionally defined compound, i.e., a “non-steroidal compound that selectively inhibits activity” of the gene product for that enzyme).
In regards to claims to a product defined by function, without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 at1568 USPQ2d at 1406 (“definition by function…does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
The instant specification fails to provide sufficient descriptive information, such as definitive structural features that are common to the genera. That is, the specification provides neither a representative number of members encompass the genera nor does it provide a description of structural features that are common to the genera so that one of skill in the art can ‘visualize or recognize’ the members of the genera. “[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. Further, in view of Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017) and the Office’s February 2018 memo clarifying written description guidance for claims drawn to antibodies, the 2008 Written Description Training Materials are outdated and should not be relied upon as reflecting the current state of law regarding 35 U.S.C. 112. Further, a “newly characterized antigen” test flouts basic legal principles of the written description requirement (Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017)). Adequate written description of a newly characterized antigen alone is not considered adequate written description of a claimed antibody to that newly characterized antigen. Where an antibody binds to an antigen tells one nothing about the structure of any other antibody. Also, see the Board’s decision in Appeal 2017-010877 (claims to “A monoclonal antibody that binds a conformational epitope formed by amino acids 42-66 of SEQ ID NO:1”).
The functional requirements of the claimed antibodies is the sort of wish list of properties which fails to satisfy the written description requirement because “antibodies with those properties have not been adequately described.” Centocor, 636 F.3d at 1352. The “claims merely recite a description of the problem to be solved while claiming all solutions to it and . . . cover any compound later actually invented and determined to fall within the claim’s functional boundaries— leaving it to the pharmaceutical industry to complete an unfinished invention.”Ariad Pharmaceuticals, Inc. v. EliLilly and Co.,598 F.3d 1336, 1353 (Fed. Cir. 2010).
Since the disclosure fails to describe common attributes or characteristics that adequately identify members of the genera, and because the genera are highly variant, the disclosure is insufficient to describe the genera. Thus, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genera as broadly claimed.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “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). As discussed above, even though Applicant may propose methods of screening for possible members of the genera, the skilled artisan cannot envision the detailed chemical structure of the encompassed genera, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolation. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. See Ariad, 94 USPQ2d at 1161; Centocor at 1876 (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”)
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
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, 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.
Claims 44 and 50 are rejected under 35 U.S.C. 103(a) as being unpatentable over Geuijen et al (WO 2019/031965; 2/19/14) in view of Jin et al (Bispecific Antibodies, Chapter 9: “The Design and Engineering of IgG-Like Bispecific Antibodies”. In: Kontermann, R. Bispecific Antibodies. Springer, Berlin, Heidelberg, pages 151-169) and Su et al (Molecular Cancer Therapeutics, 2019, 18(1): 100-111).
Geuijen et al teaches generating bispecific antibodies comprising a cMET binding domain and an EGFR binding domain (Abstract, in particular). Bispecific antibodies of Geuijen et al required heterodimerization to be properly generated and utilized knobs-into-holes in order to increase the percentage of bispecific antibodies that were properly generated (lines 26-28 on page 20, in particular). Geuijen et al further teaches bispecific antibodies that bind both cMET and EGFR provide therapeutic benefit when administered to subjects with tumors (Example 6 and figures 22-23, in particular). Geuijen et al further mentions the well-known anti-EGFR IgG antibodies cetuximab and panitumumab (lines 39-40, in particular).
Geuijen et al does not specifically teach a bispecific antibody with a structure of instant claim 44, which comprises VHH domains specific for c-MET and VH/VL domains specific for EGFR. However, these deficiencies are made up in the teachings of Jin et al and Su et al.
Fig. 9.1 of Jin et al teaches IgG, Fc, scFv, and sVD domains as building blocks for bispecific antibodies:
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Fig. 9.1 of Jin et al further teaches bispecific antibodies with an sVD domain attached N-terminally, via a linker, to each heavy chain of an IgG comprising the following general structure:
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Jin et al further teaches sVD domain include camelid VH domains (paragraph spanning pages 160-161, in particular).
Su et al teaches sVD domain camelid VH domains (“VHH”) that bind cMET (Abstract, in particular). Su et al further teaches the sVD domain camelid VH domains that bind cMET block kinase activity of cMET, reduce protein level of cMET, dramatically suppress cancer cell proliferation in vitro, and inhibit tumorigenesis and growth in mice (Abstract, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of generating bispecific antibodies comprising a cMET binding domain and an EGFR binding domain of Geuijen et al for treating tumors wherein the bispecific antibodies comprise the sVD-IgG structure of Jin et al wherein the scVD domains of the bispecific antibodies bind one antigen (such as cMET) and the IgG domains of the bispecific antibodies bind the other antigen (such as EGFR) because the sVD-IgG construct has the benefit of avoiding mismatched FC domains because, unlike constructs of Geuijen et al that require heterodimerization of FC domains, cells recombinantly expressing sVD-IgG would have the benefit of just any recombinant heavy chain dimerizing with any other recombinant heavy chain because the heavy chains are identical and EGFR IgGs and sVD domains that therapeutically target cMET are known in the prior art.
Further, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform said combined method wherein cells generating the antibodies express heavy chains where the N-terminal scVD domains are different and the heavy chains are permitted to both homodimerize (into bispecific antibodies) and heterodimerize (into tri-specific antibodies) because such tri-specific antibodies would comprise two different cMET-binding sVD binding domains and Su et al teaches combinations (“pools”) of sVD camelid VH domains that bind cMET block kinase activity of cMET, reduce protein level of cMET, dramatically suppress cancer cell proliferation in vitro, and inhibit tumorigenesis and growth in mice (Abstract, in particular).
This is an example of combining prior art elements according to known methods to yield predictable results. This is further an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Conclusion
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/SEAN E AEDER/Primary Examiner, Art Unit 1642