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
Applicant's election without traverse of the following species in the reply filed on 02/17/2026 is acknowledged:-
the P1 sequence identified by SEQ ID NO: 138;
the sequences of CDRs of A1 corresponding to: HC-CDR1: SEQ ID NO:1, HC-CDR2: SEQ ID NO: 2, HC-CDR3: SEQ ID NO: 3; LC-CDR1: SEQ ID NO: 4, LC-CDR2: SEQ ID NO: 5, and LC-CDR3: SEQ ID NO: 6;
the sequences of CDRs of B corresponding to: HC-CDR1: SEQ ID NO:10, HC-CDR2: SEQ ID NO: 11, HC-CDR3: SEQ ID NO: 12; LC- CDR1: SEQ ID NO: 13, LC-CDR2: SEQ ID NO: 14, and LC-CDR3: SEQ ID NO: 15;
the sequences of A1 corresponding to: scFv heavy chain SEQ ID NO: 7, scFv light chain SEQ ID NO: 8, and scFv SEQ ID NO: 9;
the sequences of B corresponding to: Fab heavy chain SEQ ID NO: 17 and Fab light chain SEQ ID NO: 16;
the L1 sequence corresponding to SEQ ID NO: 88;
the sequences of CDRs of H1 corresponding to: HC-CDR1: SEQ ID NO:54, HC-CDR2: SEQ ID NO: 55, and HC-CDR3: SEQ ID NO: 56; and
the isolated multispecific antibody comprising an amino acid sequence corresponding to SEQ ID NOs: 165 and 166.
For the purpose of compact prosecution, the Examiner has rejoined all species of P1, L1, A1 and B for examination under the merits in this Office Action.
Status of Claims
Claims 1-3, 6, 11, 27, 31, 33, 59, 60, 62, 63, 65, 70, 75, 80, 85, 94, 121 and 151 are pending.
Claims 11, 63 and 121 are amended.
Claims 1-3, 6, 11, 27, 31, 33, 59, 60, 62, 63, 65, 70, 75, 80, 85, 94, 121 and 151 are currently under examination on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The U.S. effective filing date of all claims under examination is set at 05/04/2022 based on the provisional application 63/338,115 (filed 05/04/2022).
Information Disclosure Statement
The information disclosure statements (IDS) submitted are being considered by the examiner.
Specification
The disclosure is objected to because of the following informalities:
Pg 149 last line: the term “IFNy” appears to be a typographical error which should be amended to “IFNγ”; and
Pg 155 line 3: the phrase “Table 20” appears to be a typographical error which should be amended to “Table "25".
Appropriate correction is required.
Claim Objections
Claims 11, 59 and 62 are objected to because of the following informalities:
Claim 11 appears to have a typographical error. The term “A1” in line three should be amended to “A1”.
Claim 59 appears to have a typographical error. The word “and” is suggested to be inserted in line 5 so that the claim recites “….HC-CDR2: SEQ ID NO: 2; and HC-CDR3: SEQ ID NO: 3.”
Claim 62 appears to have a typographical error. The word “and” is suggested to be inserted in line 5 so that the claim recites “….HC-CDR2: SEQ ID NO: 11; and HC-CDR3: SEQ ID NO: 12.”
Claim Rejections 35 U.S.C.112(a) – (First)
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 1-3, 6, 11, 27, 31, 33, 59, 60-62, 63, 65, 70, 75, 80, 85, 94, 121 and 151 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 following genus have been noted:-
claims 1-3, 6, 11, 27, 31, 33, 59, 60, 62, 63, 65, 70, 80, 85, 94 and 121 are inclusive of a genus of P1 that binds to each possible A1 (CD28 binding domain) encompassed by the claims;
claim 59 is inclusive of a genus of CD28 binding domain (A1) comprising a scFv heavy chain variable domain comprising HC-CDR1: SEQ ID NO: 1; HC-CDR2: SEQ ID NO: 2; and HC-CDR3: SEQ ID NO: 3 paired with an undefined scFv light chain variable domain LC-CDR1, LC-CDR2, and LC-CDR3;
Claim 60 is inclusive of a genus of CD28 binding domain (A1) comprising a scFv light chain variable domain comprising LC-CDR1: SEQ ID NO: 4; LC-CDR2:SEQ ID NO: 5 (KA); and LC-CDR3: SEQ ID NO: 6 paired with an undefined scFv heavy chain variable domain HC-CDR1, HC-CDR2, and HC-CDR3;
Claim 65 is inclusive of a genus of CD28 binding domain (A1) comprising a scFv heavy chain variable domain comprising an amino acid sequence that has at least 90% sequence identity to the amino acid sequence according to SEQ ID NO: 7, which includes mutations of up to 10% in the heavy chain variable domain CDR regions responsible for providing the function of binding to CD28, paired with an undefined scFv light chain variable domain;
Claim 70 is inclusive of a genus of CD28 binding domain (A1) comprising a scFv light chain variable domain comprising an amino acid sequence that has at least 90% sequence identity to the amino acid sequence according to SEQ ID NO: 8, which includes mutations of up to 10% in the light chain variable domain CDR regions responsible for providing the function of binding to CD28, paired with an undefined scFv heavy chain variable domain;
Claim 75 is inclusive of a genus of CD28 binding domain (A1) comprising a scFv comprising an amino acid sequence that has at least 90% sequence identity to the amino acid sequence according to SEQ ID NO: 9, which includes mutations of up to 10% in the light chain variable domain CDR regions and/or the heavy chain variable domain CDR regions responsible for providing the function of binding to CD28;
Claim 62 is inclusive of a genus of PD-L1 binding domain (B) comprising a Fab heavy chain variable domain comprising HC-CDR1: SEQ ID NO: 10; HC-CDR2: SEQ ID NO: 11; and HC-CDR3: SEQ ID NO: 12 paired with an undefined Fab light chain variable domain LC-CDR1, LC-CDR2, and LC-CDR3;
Claim 63 is inclusive of a genus of PD-L1 binding domain (B) comprising a Fab light chain variable domain comprising LC-CDR1: SEQ ID NO: 13; LC-CDR2: SEQ ID NO: 14 (DA); and LC-CDR3: SEQ ID NO: 15 paired with an undefined Fab heavy chain variable domain HC-CDR1, HC-CDR2, and HC-CDR3;
Claim 80 is inclusive of a genus of PD-L1 binding domain (B) comprising a Fab heavy chain polypeptide comprising an amino acid sequence that has at least 90% sequence identity to the amino acid sequence according to SEQ ID NO: 17, which includes mutations of up to 10% in the heavy chain polypeptide CDR regions responsible for providing the function of binding to PD-L1, paired with an undefined Fab light chain polypeptide;
Claim 85 is inclusive of a genus of PD-L1 binding domain (B) comprising a Fab light chain polypeptide comprising an amino acid sequence that has at least 90% sequence identity to the amino acid sequence according to SEQ ID NO: 16, which includes mutations of up to 10% in the light chain polypeptide CDR regions responsible for providing the function of binding to PD-L1, paired with an undefined Fab heavy chain polypeptide;
Claim 151 is inclusive of a genus of multispecific antibody comprising an amino acid sequence that has at least 95% sequence identity to the amino acid sequence according to SEQ ID NOs: 165 and 166, which includes mutations of up to 5% in the CDR regions responsible for providing the function of binding to CD28 and in the CDR regions responsible for providing the function of binding to PD-L1.
The written description in this case sets forth one species of anti-CD28 scFv comprising the amino acid sequence as set forth in SEQ ID NO: 9, wherein the heavy chain variable domain sequence is as set forth in SEQ ID NO: 7 which comprises HC-CDR1: SEQ ID NO: 1, HC-CDR2: SEQ ID NO: 2 and HC-CDR3: SEQ ID NO: 3, and wherein the light chain variable domain sequence is as set forth in SEQ ID NO: 8 which comprises LC-CDR1: SEQ ID NO: 4, LC-CDR2:SEQ ID NO: 5 (KA) and LC-CDR3: SEQ ID NO: 6 (Table 4 on Pg 35 and Table 8 on Pg 37), capable of binding to CD28 as well as being able to bind a library of P1 peptides (Table 1 on Pg 31, Table 20 on Pg 128-146, Figures 3-6 and Figures 8-10 and Tables 18 and 19). Further, the written description in this case also sets forth one species of PD-L1 Fab comprising the heavy chain polypeptide sequence as set forth in SEQ ID NO: 17 which comprises HC-CDR1: SEQ ID NO: 10, HC-CDR2: SEQ ID NO: 11 and HC-CDR3: SEQ ID NO: 12, and comprising the light chain variable domain sequence as set forth in SEQ ID NO: 16 which comprises LC-CDR1: SEQ ID NO: 13, LC-CDR2: SEQ ID NO: 14 (DA) and LC-CDR3: SEQ ID NO: 15 (Tables 6 and 7 on Pg 36 and Table 9 on Pg 38). It is noted that Ab-12, shown in Figures 3B-3F, Figures 4C and 4D, Figures 9A-9C and Table 19 for its ability to bind P1 and in turn having the ability to inhibit the CD28 binding domain from binding to CD28, is a CD28 x PD-L1 antibody that comprises SEQ ID NO: 9 (CD28 binding domain) and SEQ ID NOs: 16 and 17 (PD-L1 binding domain). It is further noted that the other antibodies that bind to CD28 and PD-L1 shown in Tables 10 and 12, namely Ab-1 to Ab-11, Ab-13, JXA2616, JXA2618 and JXA3777, also comprise the one species of CD28 binding domain comprising SEQ ID NO 9 and the one species of PD-L1 binding domain comprising SEQ ID NOs: 16 and 17.
Only one species of CD28 binding domain (A1) encompassed by the claims comprising SEQ ID NO: 9 was shown to bind P1 and only one species of PD-L1 (B) encompassed by the claims comprising SEQ ID NOs: 17 and 16 was disclosed to be combined with SEQ ID NO: 9 to form multispecific antibodies (sixteen species but all with the same CD28 scFv and PD-L1 Fab), such that only one set of six CDRs comprising HC-CDR1: SEQ ID NO: 1, HC-CDR2: SEQ ID NO: 2 and HC-CDR3: SEQ ID NO: 3, paired with LC-CDR1: SEQ ID NO: 4, LC-CDR2:SEQ ID NO: 5 (KA) and LC-CDR3: SEQ ID NO: 6, or one set of VH and VL pairing of SEQ ID NOs: 7 and 8 respectively, was disclosed for the CD28 binding domain; and only one set of six CDRs comprising HC-CDR1: SEQ ID NO: 10, HC-CDR2: SEQ ID NO: 11 and HC-CDR3: SEQ ID NO: 12, paired with LC-CDR1: SEQ ID NO: 13, LC-CDR2: SEQ ID NO: 14 (DA) and LC-CDR3: SEQ ID NO: 15, or one set of VH and VL pairing of SEQ ID NOs: 17 and 16 respectively, was disclosed for the PD-L1 binding domain. The specification does not disclose, and the art does not teach, the genus of A1, B and multispecific antibody as broadly as is encompassed in the claims.
As is well-known in the antibody art at the time of filing, the specificity of an antibody is dependent upon the six CDR regions and different combinations of CDR sequences greatly alter antigen binding. It is well established 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 which provide the majority of the contact residues for the binding of the antibody to its target epitope (reviewed in Sela-Culang et al. Frontiers in immunology 4 (2013): 302). 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. 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. teaches 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. Therefore, there is insufficient evidence or nexus that would lead the skilled artisan to predict the ability of a scFv to bind to CD28 or a Fab to bind to PD-L1 comprising mutations in any of the six CDR regions, or comprising mixing and matching a known set of three CDRs with an undefined set of three CDRs, which is also a form of introducing mutations into the CDR regions.
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.
Regarding 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 genus. That is, the specification provides neither a representative number of species antigen binding proteins that encompass the genus nor does it provide a description of structural features that are common to the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus. “[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.
The functional requirements of the claimed antibodies are 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. Eli Lilly 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 genus, and because the genus is highly variant, the disclosure of ONE SPECIES found in the specification for of A1 and ONE SPECIES found in the specification for B that are comprised in the sixteen multispecific antibodies found in the specification is insufficient to describe the genus. Thus, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus 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 genus, 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 U.S.C.112(a) – (Second)
Claims 1-3, 6, 11, 27, 31, 33, 59, 60, 62, 63, 65, 70, 75, 80, 85, 94, 121 and 151 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 making and using a multispecific antibody encompassed by the claims comprising P1 that binds to A1 wherein A1 comprises a CD28 binding domain as set forth in SEQ ID NO: 9, does not reasonably provide enablement for A1 that is just any CD28 binding domain. 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 and use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required are summarized in Ex parte Forman, 230 USPQ 546 (BPAI 1986). They include the nature of the invention, the state of the prior art, the relative skill of those in the art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the predictability or unpredictability of the art, the breadth of the claims, and the quantity of experimentation which would be required in order to practice the invention as claimed.
The nature of the invention
The instant claims are drawn to CD28 binding domains such that there are numerous known in the art, that also can be bound by the 14-mer P1 peptide according to the amino acid sequence X1-X2-X3-C-X4-X5-X6-X7-X-X9-X10-C-X11-X12, wherein P1 is a genus as recited in claim 1 comprising up to three to thirteen possible amino acid residues for the X1 to X12 positions.
The breadth of the claims
The claims are broad in that they encompass the numerous CD28 binding domains known in the prior art. Further, the claims are broad because:-
in claims 1, 11, 27, 31, 33, 59, 60, 62, 63, 65, 70, 75, 80, 85, 94, 121 and 151, there are 4x9x3x3x13x12x6x2x11x13x5x9 = 3,903,007680 possibilities of P1;
in claim 2, there are 3x4x1x1x6x6x3x1x6x5x3 = 583,200 possibilities of P1;
in claim 3, there are 1x2x1x1x3x3x3x1x4x5x1x3 = 3,240 possibilities of P1; and
in claim 6, wherein P1 comprises an amino acid sequence that has 1, 2, or 3 amino acid mutations, substitutions, or deletions relative to instant SEQ ID NO: 138, there are also at least several hundred possibilities of P1,
wherein the different possibilities of P1 potentially could also result in peptides that bind to CD28 binding domains other than instant SEQ ID NO:9.
The amount of direction provided by the inventor/the existence of working examples
The specification discloses only one species of anti-CD28 scFv comprising the amino acid sequence as set forth in SEQ ID NO: 9, wherein the heavy chain variable domain sequence is as set forth in SEQ ID NO: 7 which comprises HC-CDR1: SEQ ID NO: 1, HC-CDR2: SEQ ID NO: 2 and HC-CDR3: SEQ ID NO: 3, and wherein the light chain variable domain sequence is as set forth in SEQ ID NO: 8 which comprises LC-CDR1: SEQ ID NO: 4, LC-CDR2:SEQ ID NO: 5 (KA) and LC-CDR3: SEQ ID NO: 6 (Table 4 on Pg 35 and Table 8 on Pg 37), capable of binding to CD28 as well as being able to bind a library of P1 peptides (Table 1 on Pg 31, Table 20 on Pg 128-146, Figures 3-6 and Figures 8-10 and Tables 18 and 19).
The state of the art/the level of predictability in the art
The state of the art teaches that predicting protein-peptide interactions can be difficult experimentally. The art teaches that screening phage peptide libraries have resulted in the identification of sequences that specifically bind to desired targets, for example, Zhang et al. teaches identification of the peptide, NWYLPWLGTNDW, that specifically binds to human monocytes and macrophages upon screening of random phage peptide libraries (Abstract; Zhang et al. Int J Mol Sci. 2022 Apr 13;23(8):4282, 1-20). Zhang et al. further teaches that single replacement of either tryptophan or leucine with alanine completely inhibited binding, whereas the replacement of asparagine at position 1 or 10 and aspartic acid at position 11 with alanine did not affect the binding of the peptide variants, while neutral amino acid replacement of tryptophan at positions 2, 6, and 12 with tyrosine or phenylalanine also abolished the binding (Abstract and Figures 6 and 7). Therefore, it can be concluded that the effects of amino acid mutations on the binding of a peptide is highly unpredictable.
Further, because experimentally predicting protein-peptide interactions can be difficult, computational methods have been established for making such predictions (Abstract; Johansson-Åkhe et al. Sci Rep 9, 4267 (2019); 1-13). Johansson-Åkhe et al. teaches that the InterPep software was successful at pinpointing 255 of 502 (50.7%) binding sites in experimentally determined structures at rank 1; and 348 of 502 (69.3%) among the top five predictions, when using only structures with no significant sequence similarity as templates (Abstract and Fig 7). Therefore, predictions of protein-peptide interactions ranged between 50 to 70% at best from the prediction software of Johansson-Åkhe et al., again confirming the high unpredictability of determining protein-peptide interactions.
In summary, this invention is in a class of invention which the CAFC has characterized as "the unpredictable arts such as chemistry and biology". Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
Based on the instant disclosure and prior art, there is no known method through which one of ordinary skill in the art would have been able to reliably predict or otherwise envisage all possible CD28 binding domains that would be able to bind to the numerous P1 peptide genus as recited in the claims. Therefore, in order to practice the invention as claimed, one of ordinary skill in the art would have to perform undue experimentation to create and function test all CD28 binding domains and all possible P1 peptide variants that can function to bind to the various CD28 binding domains known in the art.
The Examiner confirms that Applicant is enabled for the CD28 binding scFv as set forth in instant SEQ ID NO: 9 that the P1 peptide variants or genus recited in the claims can bind to.
Conclusion
One cannot extrapolate the teachings of the specification to the scope of the claims because the claims are broadly drawn to any CD28 binding domain, and Applicant is not enabled because it has not been shown that P1 peptide variants or genus recited in the claims can bind to any CD28 binding domain except instant SEQ ID NO: 9.
In view of the teachings above and the lack of guidance, workable examples and or exemplification in the specification, it would require an unreasonable amount of experimentation by one of skill in the art to determine with any predictability, that the method would function as claimed.
Claim Rejections 35 U.S.C.112(a) – (Third)
Claims 65, 70, 75, 80, 85 and 151 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 (i) a CD28 binding domain comprising SEQ ID NOs: 7 and 8 or SEQ ID NO: 9; (ii) a PD-L1 binding domain comprising SEQ ID NOs: 17 and 16; or (iii) a multispecific antibody comprising SEQ ID NOs: 165 and 166, does not reasonably provide enablement for (i) a CD28 binding domain comprising at least 90% sequence identity to SEQ ID NOs: 7 and/or 8, or a CD28 binding domain comprising at least 90% sequence identity to SEQ ID NO: 9; (ii) a PD-L1 binding domain comprising at least 90% sequence identity to SEQ ID NOs: 17 and/or 16; or (iii) a multispecific antibody comprising at least 95% sequence identity to SEQ ID NOs: 165 and 166. 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 and use the invention commensurate in scope with these claims.
The nature of the invention
Claim 65 is drawn to CD28 binding scFv’s comprising instant SEQ ID NO: 7 for the heavy chain variable domain, and with up to 10% mutations in and around the heavy chain CDR sequences, as well as undefined light chain CDR sequences which is equivalent to mutations in and around the light chain CDR sequences.
Claim 70 is drawn to CD28 binding scFv’s comprising instant SEQ ID NO: 8 for the light chain variable domain, and with up to 10% mutations in and around the light chain CDR sequences, as well as undefined heavy chain CDR sequences which is equivalent to mutations in and around the heavy chain CDR sequences.
Claim 75 is drawn to CD28 binding scFv’s comprising instant SEQ ID NO: 9, as well as up to 10% mutations in and around the heavy chain CDR sequences and/or the light chain CDR sequences.
Claim 80 is drawn to PD-L1 binding Fab’s comprising instant SEQ ID NO: 17 for the heavy chain polypeptide, and with up to 10% mutations in and around the heavy chain CDR sequences, as well as undefined light chain CDR sequences which is equivalent to mutations in and around the light chain CDR sequences.
Claim 85 is drawn to PD-L1 binding Fab’s comprising instant SEQ ID NO: 16 for the light chain polypeptide, and with up to 10% mutations in and around the light chain CDR sequences, as well as undefined heavy chain CDR sequences which is equivalent to mutations in and around the heavy chain CDR sequences.
Claim 151 is drawn to multispecific antibodies comprising instant SEQ ID NOs: 165 and 166, as well as with up to 5% mutations in and around the CDR sequences of the CD28 binding domain and/or the PD-L1 binding domain.
The breadth of the claims
The claims are broad in that they encompass mutants with up to 10% mutations in the CDRs of SEQ ID NOs: 7, 8 and 9 of the CD28 binding domain; or with up to 10% mutations in the CDRs of SEQ ID NOs: 17 and 16 of the PD-L1 binding domain; or with up to 5% mutations the CDRs of SEQ ID NOs: 165 and 166 of the multispecific antibody, that would retain the function of binding to their respective target antigens.
In addition, for claim 65, the undefined CD28 binding light chain variable domain is equivalent to any amount of mutations in and around the light chain CDR sequences. For claim 70, the undefined CD28 binding heavy chain variable domain is equivalent to any amount of mutations in and around the heavy chain CDR sequences. For claim 80, the undefined PD-L1 binding light chain polypeptide is equivalent to any amount of mutations in and around the light chain CDR sequences. For claim 85, the undefined PD-L1 binding heavy chain polypeptide is equivalent to any amount of mutations in and around the heavy chain CDR sequences.
The amount of direction provided by the inventor/the existence of working examples
The specification discloses only one species of anti-CD28 scFv comprising the amino acid sequence as set forth in SEQ ID NO: 9, wherein the heavy chain variable domain sequence is as set forth in SEQ ID NO: 7 which comprises HC-CDR1: SEQ ID NO: 1, HC-CDR2: SEQ ID NO: 2 and HC-CDR3: SEQ ID NO: 3, and wherein the light chain variable domain sequence is as set forth in SEQ ID NO: 8 which comprises LC-CDR1: SEQ ID NO: 4, LC-CDR2:SEQ ID NO: 5 (KA) and LC-CDR3: SEQ ID NO: 6 (Table 4 on Pg 35 and Table 8 on Pg 37), capable of binding to CD28 as well as being able to bind a library of P1 peptides (Table 1 on Pg 31, Table 20 on Pg 128-146, Figures 3-6 and Figures 8-10 and Tables 18 and 19).
The specification also only discloses one species of PD-L1 Fab comprising the heavy chain polypeptide sequence as set forth in SEQ ID NO: 17 which comprises HC-CDR1: SEQ ID NO: 10, HC-CDR2: SEQ ID NO: 11 and HC-CDR3: SEQ ID NO: 12, and comprising the light chain variable domain sequence as set forth in SEQ ID NO: 16 which comprises LC-CDR1: SEQ ID NO: 13, LC-CDR2: SEQ ID NO: 14 (DA) and LC-CDR3: SEQ ID NO: 15 (Tables 6 and 7 on Pg 36 and Table 9 on Pg 38).
Further, the specification discloses in Table 12 on Pg 49 and 50, the multispecific CD28 x PD-L1 antibody named Ab-9 comprising SEQ ID NOs: 165 and 166. Sequence alignment shows that Ab-9 comprises SEQ ID NO: 9 (CD28 binding domain) and SEQ ID NOs: 16 and 17 (PD-L1 binding domain). It is further noted that the other antibodies that bind to CD28 and PD-L1 shown in Tables 10 and 12, namely Ab-1 to Ab-8, Ab-10 to Ab-13, JXA2616, JXA2618 and JXA3777, also comprise the one species of CD28 binding domain comprising SEQ ID NO 9 and the one species of PD-L1 binding domain comprising SEQ ID NOs: 17 and 16.
Therefore, the disclosure does not discuss, or demonstrate through working examples, any novel mutants of the CD28 binding domain comprising SEQ ID NO: 9; or the PD-L1 binding domain comprising SEQ ID NOs: 17 and 16; or the multispecific antibody comprising SEQ ID NOs: 165 and 166, that retain the instant claimed functionalities.
The state of the art/the level of predictability in the art
The state of the art teaches that with regards to changes in the amino acid residues on binding domains, it is especially important to disclose which residues are permissive to mutation. 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 USA, Vol., 79, Pg. 1979-1983, 1982, see Abstract). Further, an enabling disclosure for the preparation and use of only a few analogs of a product does not enable all possible analogs where the characteristics of the analogs are unpredictable. See Amgen Inc. v. Chugai Pharmaceutical Co. Ltd. (18 USPQ 2d 1027 (CAFC 1991)).
Not knowing and absent further experimentation, which modifications can retain antigen binding function and which cannot, even a single change of an encoded amino acid can unpredictably affect structure and function, leads to one having no predictability or expectation of success for the function of any given antibody modification. Such random experimentation to identify at a later time what structure or modification is or is not functional and is embraced by Applicant’s claims is undue experimentation.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
Based on the instant disclosure and prior art, there is no known method through which one of ordinary skill in the art would have been able to reliably predict or otherwise envisage all possible mutations in the CDR regions of SEQ ID NOs: 7, 8 and 9 (CD28 binding domain); or SEQ ID NOs: 17 and 16 (PD-L1 binding domain); or SEQ ID NOs: 165 and 166 (multispecific antibody) that would retain their respective binding functions. Therefore, in order to practice the invention as claimed, one of ordinary skill in the art would have to perform undue experimentation to create and function test all possible mutations on the CD28 binding domain, PD-L1 binding domain and multispecific antibody for retention of their respective functional activities.
The Examiner confirms that Applicant is enabled for a CD28 binding domain that comprises SEQ ID NO: 9; a PD-L1 binding domain that comprises SEQ ID NOs: 17 and 16; and a multispecific antibody that comprises SEQ ID NOs: 165 and 166, or that comprises SEQ ID NOs: 9, 17 and 16.
Conclusion
In view of the Wands factors as discussed above, one of ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the instant claimed invention. This is because the art teaches that it is unpredictable whether or not CDR variants of known antibodies or binding domains will function as such, and the specification does not provide direction on which constructs below 100% identity have function, or do not have function, as claimed in order to perform the method as claimed. In other words, the specification does nothing to ameliorate these concerns over the breadth of the claims rejected above with respect to functional variants, therefore, one would be burdened with undue experimentation to make or use the products of instant claims as broadly as they are currently claimed.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Yie-Chia Lee (Tonya) whose telephone number is (571)272-0123. The examiner can normally be reached Monday - Friday 7.30a - 3.30p Eastern Time Zone.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached on 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/YIE-CHIA LEE (TONYA)/Examiner, Art Unit 1642
/SEAN E AEDER/Primary Examiner, Art Unit 1642
Prosecution Insights