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 3/9/26 to the restriction requirement of 1/7/26 has been received. Without travers, Applicant has elected the following species: SEQ ID NOs: 1-7, 11, 15, 19, and 25 as disclosed polypeptide sequence of a distinct antibody or antigen binding fragment thereof encompassed by the claims, encoded by claimed polynucleotides, made by claimed methods, and/or administered by claimed methods.
Claims 1-12, 14, 15, 18-27, 29-39, 41-52, 56-97, 102, and 103 are pending.
Claims 18-27 and 29-31 are withdrawn from further consideration by the examiner under 37 CFR 1.142(b) as being drawn to a non-elected invention.
Claims 1-12, 14, 15, 32-39, 41-52, 56-97, 102, and 103 are 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 1-7, 11, 14, 32-39, 41-43, 45-51, 56-61, 63-97, 102, and 103 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: (1) a genus of antibodies, antigen-binding fragments thereof, and scFv antibodies comprising (a) a heavy chain CDR1 comprising just any sequence selected from SEQ ID NOs: 1, 27, and 43, (b) a heavy chain CDR2 comprising just any sequence selected from SEQ ID NOs: 2, 28, and 44, (c) a heavy chain CDR3 comprising just any sequence selected from SEQ ID NOs: 3, 29, and 45, (d) a light chain CDR1 comprising just any sequence selected from SEQ ID NOs: 4, 30, and 46, (e) a light chain CDR2 comprising just any sequence selected from SEQ ID NOs: 5, 31, and 47, and (f) a light chain CDR3 comprising just any sequence selected from SEQ ID NOs: 6, 32, and 40 (see claims 1 and 42); (2) a genus of antibodies, antigen-binding fragments thereof, and scFv antibodies comprising a heavy chain variable region comprising any amino acid sequence with as little as 80% identity to any sequence selected from SEQ ID NOs: 7, 9, 33, and 49; and a light chain variable region comprising any amino acid sequence with as little as 80% identity to any sequence selected from SEQ ID NOs: 11, 35, and 51 (see claims 4 and 43); (3) a genus of antibodies or antigen-binding fragments thereof comprising a heavy chain variable region comprising any sequence selected from SEQ ID NOs: 7, 9, 33, and 49; and a light chain variable region comprising any sequence selected from SEQ ID NOs: 11, 35, and 51 (see claim 5); (4) a genus of antibodies or antigen-binding fragments thereof comprising a heavy chain comprising any amino acid sequence with as little as 80% identity to any sequence selected from SEQ ID NOs: 18, 21, 23, 39, and 55; and a light chain comprising any amino acid sequence with as little as 80% identity to any sequence selected from SEQ ID NOs: 25, 41, and 57 (see claim 6); (5) a genus of antibodies or antigen-binding fragments thereof comprising a heavy chain comprising any amino acid sequence selected from SEQ ID NOs: 18, 21, 23, 39, and 55; and a light chain comprising any sequence selected from SEQ ID NOs: 25, 41, and 57 (see claim 7); (6) a genus of antibodies or antigen-binding fragments thereof comprising a heavy chain variable region comprising any amino acid sequence with as little as 80% identity to any sequence selected from SEQ ID NOs: 7 and 9; and a light chain variable region comprising any amino acid sequence with as little as 80% identity to SEQ ID NOs: 11 (see claim 11); (7) a genus of antibodies or antigen-binding fragments thereof comprising a heavy chain comprising any amino acid sequence with as little as 80% identity to any sequence selected from SEQ ID NOs: 19, 21, and 23; and a light chain comprising any amino acid sequence with as little as 80% identity to SEQ ID NOs: 25 (see claim 14); (8) a genus of canine antibodies and antigen-binding fragments thereof that specifically bind to canine programmed death protein 1 (see claim 39); (9) a genus of canine antibodies and antigen-binding fragments thereof that specifically bind to canine programmed death protein 1 (cPD-1) and disrupts the interaction of cPD-1 and just any ligand of cPD-1 (see claim 41); (10) a genus of isolated nucleic acids encoding antibodies and antigen-binding fragments thereof, wherein the antibodies or antigen-binding fragments thereof comprise (a) a heavy chain variable region encoded by any nucleic acid comprising any polynucleotide sequence with as little as 80% identity to any sequence selected from SEQ ID NOs: 8, 10, 34, and 50, and (b) a light chain variable region encoded by any nucleic acid comprising any polynucleotide sequence with as little as 80% identity to any sequence selected from SEQ ID NOs: 12, 36, and 52 (see claim 49); (11) a genus of isolated nucleic acids encoding an scFv antibody comprising (a) a heavy chain variable region encoded by any nucleic acid comprising any polynucleotide sequence selected from SEQ ID NOs: 8, 10, 34, and 50, and (b) a light chain variable region encoded by any nucleic acid comprising any polynucleotide sequence selected from SEQ ID NOs: 12, 36, and 52 (see claim 61); (12) a genus of isolated nucleic acids encoding an scFv antibody that specifically binds to cPD-1 comprising (a) a heavy chain variable region encoded by any nucleic acid comprising any polynucleotide sequence selected from SEQ ID NOs: 8, 10, 34, and 50, and (b) a light chain variable region encoded by any nucleic acid comprising any polynucleotide sequence selected from SEQ ID NOs: 12, 36, and 52 (see claim 63); (13) a genus of antibodies and antigen-binding fragments thereof that specifically bind cPD-1 comprising (a) a heavy chain CDR1 comprising just any sequence selected from SEQ ID NOs: 1, 27, and 43, (b) a heavy chain CDR2 comprising just any sequence selected from SEQ ID NOs: 2, 28, and 44, (c) a heavy chain CDR3 comprising just any sequence selected from SEQ ID NOs: 3, 29, and 45, (d) a light chain CDR1 comprising just any sequence selected from SEQ ID NOs: 4, 30, and 46, (e) a light chain CDR2 comprising just any sequence selected from SEQ ID NOs: 5, 31, and 47, and (f) a light chain CDR3 comprising just any sequence selected from SEQ ID NOs: 6, 32, and 40 (see claim 91); and (14) a genus of antibodies and antigen-binding fragments thereof that specifically bind cPD-1 and disrupt interaction of cPD-1 and just any ligand of cPD-1 comprising (a) a heavy chain CDR1 comprising just any sequence selected from SEQ ID NOs: 1, 27, and 43, (b) a heavy chain CDR2 comprising just any sequence selected from SEQ ID NOs: 2, 28, and 44, (c) a heavy chain CDR3 comprising just any sequence selected from SEQ ID NOs: 3, 29, and 45, (d) a light chain CDR1 comprising just any sequence selected from SEQ ID NOs: 4, 30, and 46, (e) a light chain CDR2 comprising just any sequence selected from SEQ ID NOs: 5, 31, and 47, and (f) a light chain CDR3 comprising just any sequence selected from SEQ ID NOs: 6, 32, and 40 (see claim 91).
However, the written description in this case only sets forth: antibodies, antigen-binding fragments thereof, scFvs, and polynucleotides encompassed by the genera wherein the antibodies, antigen-binding fragments thereof, and scFvs comprise (and wherein polynucleotides of the genera comprise sequences encoding antibodies, antigen-binding fragments thereof or scFv comprising): (i) an HCDR1 comprising SEQ ID NO:1, an HCDR2 comprising SEQ ID NO:2, an HCDR3 comprising SEQ ID NO:3, an LCDR1 comprising SEQ ID NO:4, an LCDR2 comprising SEQ ID NO:5, and an LCDR3 comprising SEQ ID NO:6; (ii) an HCDR1 comprising SEQ ID NO:27, an HCDR2 comprising SEQ ID NO:28, an HCDR3 comprising SEQ ID NO:29, an LCDR1 comprising SEQ ID NO:30, an LCDR2 comprising SEQ ID NO:31, and an LCDR3 comprising SEQ ID NO:32; or (iii) an HCDR1 comprising SEQ ID NO:43, an HCDR2 comprising SEQ ID NO:44, an HCDR3 comprising SEQ ID NO:45, an LCDR1 comprising SEQ ID NO:46, an LCDR2 comprising SEQ ID NO:47, and an LCDR3 comprising SEQ ID NO:48.
One of ordinary skill in the art would recognize that the specificity of an antibody, antigen-binding fragment thereof, and scFv antibody is dependent upon the 6 CDR regions and different combinations of CDR sequences greatly alter antigen binding. It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) which provide the majority of the contact residues for the binding of the antibody to its target epitope. 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 parent 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. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff 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). Holm et al. (Molecular Immunology, 2007:1075-1084) describes the mapping of an anti-cytokeratin antibody and found that in addition to the involvement of the residues in the CDR3 of the heavy chain in antigen binding, a residue in CDR2 of the light chain was also involved (abstract). Chen et al. (Journal of Molecular Biology, 1999, 293:865-881) describe high affinity variant antibodies binding to VEGF wherein the results show that the antigen binding site is almost entirely composed of residues from heavy chain CDRs, CDR-H1, H2, H3 (page 866). There is insufficient evidence or nexus that would lead the skilled artisan to predict the ability of an antibody, antigen-binding fragment thereof, or scFv antibody to bind to function with fewer than 6 CDR regions of an antibody known to bind.
The specification does not disclose, and the art does not teach, the genera as broadly encompassed in the claims. 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 making or 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 antibodies, antigen-binding fragments thereof, scFv antibodies, or nucleic acids that 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, antigen-binding fragments thereof, and scFv 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 genus, 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 § 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.
Claim(s) 39 and 41 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Morsey et al (WO 2015/091911 A2; 6/25/15).
Morsey et teaches antibodies that specifically bind canine PD-1 (Abstract, in particular). Morsey et al further teaches said antibodies include “fully canine antibodies” that comprise canine immunoglobulin sequences only (lines 23-27 on page 31 and lines 27-28 on page 35, in particular). Morsey et al further teaches said antibodies include those wherein the antibodies block binding of canine PD-1 to the canine ligand PD-L1 (lines 28-30 on page 8, in particular).
Allowable Subject Matter
Claims 8-10, 12, 15, 44, 52, and 62 are allowed.
Conclusion
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/SEAN E AEDER/ Primary Examiner, Art Unit 1642
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