DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 22-39 are pending.
Election/Restrictions
Applicant’s election of Group I in the reply filed on April 9, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Applicant’s election of the species, A single bispecific antibody structure: Formula I;
chain 1:[VL1/VH1]-Ll-[IL15/IL15Ra]
` chain 2: [VH1/VL1]-L2-[IL15Ra/IL15]-L3-Fc
chain 3: VH2-CH1-Fc
chain 4: VL2-CL
A single IL-15 and IL-15Ra sequences: IL-15(L52C) and IL15Ra(S40C);
A single set of heterodimer mutations:
FC-A chain-T366W and FC-B chain-T366S/L368A,N407V;
A single pair of antigens: two different HER2 epitopes.
In particular, the anti-HER2 bispecific antibody QP34563457 having four peptide chains in the reply filed on April 9, 2026 is acknowledged.
Claim 39 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 27, 30 and 35 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species.
Claims 22-26, 28, 29, 31-34 and 36-38 are under examination.
Specification
The disclosure is objected to because of the following informalities:
The specification discloses that The "IL-l 5Ra" of the present invention may be IL-l5Ra of any species or a mutant capable of binding to IL l 5Ra, such as human IL-l 5Ra or non-human mammalian IL-l5Ra or non-mammalian IL-l 5Ra (page 19, lines 7-9). It is not clear how the IL-l5Ra mutant would be capable of binding to IL-l5Ra.
Appropriate correction is required.
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.
Claims 23-26, 29 and 34 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 the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 23 recites the Fc segment. However, claim 22 does not recite an Fc segment.
Claim 29 recites the limitation modifications sites of disulfide bond in VH and NL domains. There is insufficient antecedent basis for this limitation in the claim. However, claim 22 recites chain 1, chain 2, chain 3 and chain 4. It is not clear how VH and VL relate to chain 1, chain 2, chain 3 and chain 4.
Claim 34 recites the limitation “preferably, wherein the bispecific antibody is obtained by expressing fusion sequences of SEQ ID No: 10, SEQ ID No: 11, SEQ ID No: 13, SEQ ID No: 12”. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 34 recites the broad recitation “wherein the first antigen and the second antigen are antigens binding to two different epitopes of Her2”, and the claim also recites “preferably, wherein the bispecific antibody is obtained by expressing fusion sequences of SEQ ID No: 10, SEQ ID No: 11, SEQ ID No: 13, SEQ ID No: 12” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
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.
Claims 22-26, 28, 29, 31-34 and 36-38 are rejected under 35 U.S.C. 112(a), 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 claims are drawn to a bispecific antibody, which comprises: a) a first antibody that specifically binds to a first antigen; and b) a second antibody that specifically binds to a second antigen; wherein, the first antibody comprises two polypeptide chains: chain 1 and chain 2; the second antibody comprises two polypeptide chains: chain 3 and chain 4, wherein chain 3 is the heavy chain of the second antibody, and chain 4 is the light chain of the second antibody; and the first antibody and the second antibody are polymerized through chains 2 and 3; wherein the first antibody comprises IL15 and IL15Ra, and the IL15 and IL15Ra are located on two polypeptide chains of the first antibody, respectively, and are capable of forming an IL15/IL15Ra complex; and the constant domains CH1 and CL of the first antibody are replaced by the IL 15 and IL l 5Ra; the IL15 comprises the wild-type and a mutant capable of binding to IL15Ra thereof, and the IL15Ra comprises the wild-type and a mutant capable of binding to IL15 thereof.
The specification defines the term "a mutant capable of binding to IL-l5Ra" refers to a mutant molecule obtained by mutation of one or more amino acid sub substitutions, additions or deletions, with an increased or decreased affinity for IL-15 and its receptor, or with an increased or decreased activity of stimulating T cells or NK cells. The term "a mutant capable of binding to IL15Ra" refers to a functional mutant formed by one or more amino acid deletion, insertion or substitution on IL-15Ra and has the ability to bind to its ligand molecule such as IL-15, preferably a human IL-l5Ra molecule. The specification discloses several mutations of IL-15 and IL-l5Ra molecules. The specification and claim do not place any limit on the number of amino acid substitutions, deletions, insertions and/or additions that may be made to IL-15 and IL-l5Ra molecules. Thus, the scope of the claim includes numerous structural variants, and the genus is highly variant because a significant number of structural differences between genus members is permitted. Although the specification states that these types of changes are routinely done in the art, the specification and claim do not provide any guidance as to what changes could be made and IL-15 and IL-l5Ra molecules still bind IL-l5Ra and IL-15 molecules, respectively. Structural features that could distinguish compounds in the genus from others in the protein class are missing from the disclosure. No common structural attributes identify the members of the genus. The general knowledge and level of skill in the art do not supplement the omitted description because specific, not general, guidance is what is needed. Since the disclosure fails to describe the common attributes or characteristics that identify members of the genus, and because the genus is highly variant, the amino acid sequences of IL-l5Ra and IL-15 molecules alone is insufficient to describe the genus. One of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus. Thus, applicant was not in possession of the claimed genus.
The specification does not provide adequate written description of the claimed genus of IL-l5Ra mutants that were capable of binding IL-15 and IL-15 mutants that were capable of binding IL-l5Ra. The legal standard for sufficiency of a patent's (or a specification's) written description is whether that description "reasonably conveys to the artisan that the inventor had possession at that time of the. . .claimed subject matter", Vas-Cath, Inc. V. Mahurkar, 19 USPQ2d 1111 (Fed. Cir. 1991). In the instant case, the specification does not convey to the artisan that the Applicant had possession at the time of invention the genus of IL-l5Ra mutants and IL-15 mutants that were capable of binding IL-15 and IL-l5Ra, respectively.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or 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 the Applicant was in possession of the genus (Federal Register, Vol. 66, No. 4, pages 1099-1111, Fri. January 5, 2001, see especially page 1106 column 3).
The specification does not provide adequate written description of the claimed invention. The legal standard for sufficiency of a patent's (or a specification's) written description is whether that description "reasonably conveys to the artisan that the inventor had possession at that time of the. . .claimed subject matter", Vas-Cath, Inc. V. Mahurkar, 19 USPQ2d 1111 (Fed. Cir. 1991). In the instant case, the specification does not convey to the artisan that the Applicant had possession at the time of invention of the claimed invention, the genus of IL-l5Ra mutants that were capable of binding IL-15 and IL-15 mutants that were capable of binding IL-l5Ra. The genus of IL-l5Ra mutants and IL-15 mutants are claimed by function, the ability to bind to IL-15 and IL-l5Ra, respectively. The specification does not disclose any IL-l5Ra mutants and IL-15 mutants that are capable of these functions. The Federal Circuit addressed the application of the written description requirement to DNA-related inventions in University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997). The court stated that “[a] written description of an invention involving a chemical genus, like a description of a chemical species, requires a precise definition, such as by structure, formula, [or] chemical name, of the claimed subject matter sufficient to distinguish it from other materials.” Id. At 1567, 43 USPQ2d at 1405. The court concluded that “naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.” Id.
The Federal Circuit clarified that a molecule can be adequately described without disclosing its complete structure. See Enzo Biochem, Inc. V. Gen-Probe Inc., 296 F.3d 1316, 63 USPQ2d 1609 (Fed. Cir. 2002). The Enzo court adopted the standard that the written description requirement can be met by “show[ing] that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics ....i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. “ Id. At 1324, 63 USPQ2d at 1613 (emphasis omitted, bracketed material in original).
However, 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 F.3d at 1568, 43 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”).
Thus, the instant specification may provide an adequate written description of the IL-l5Ra mutants and IL-15 mutants, per Lilly by structurally describing a representative number of IL-l5Ra mutants and IL-15 mutants that were capable of binding IL-15 and IL-l5Ra or by describing structural features common to the members of the genus, which features constitute a substantial portion of the genus.
It is noted that AbbVie v. Janssen Biotech and Centocor Biologics (Fed. Cir. 2014) confirms a strong Post-Ariad Written Description requirement - especially with regard to genus-species claim situations. In the decision, Judge Lourie focuses particularly on the alleged infringing antibodies and notes that: [While] AbbVie patents need not describe the allegedly infringing [compound] in exact terms . . . [t]he patents must at least describe some species representative of antibodies that are structurally similar to [the accused compound]. Because the patent document lacked any such structural description, the court confirmed that the corresponding claims were invalid under 112(a). In discussing the case, Judge Lourie was clear that one problem here is that the invention was described in terms of its function rather than its structure. Lourie writes:
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus.
The Court has indicated in Amgen Inc vs Sanofi ( 2017-1480, Fed Cir, 2017) that the disclosure of a well characterized antigen is insufficient for an adequate written description of the antibody that binds the antigen. The Court stated that “an adequate written description must contain enough information about the actual makeup of the claim products – a precise definition such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other material,” which may be present in “function “terminology “when the art has established a correlation between structure and function” (page 17, 1st paragraph). The Court went on to indicate that knowledge of the chemical structure of an antigen does not tell you anything about the structure of the antibody (Id).
In this case, the specification does not appear to describe any IL-l5Ra mutants and IL-15 mutants that were capable of binding IL-15 and IL-l5Ra, respectively and thus does not satisfy either the Lilly nor Enzo standards. There are insufficient structural features common to all members of the genus of IL-l5Ra mutants and IL-15 mutants that were capable of binding IL-15 and IL-l5Ra. One of ordinary skill in the art would not be able to identify the broad claimed genus of IL-l5Ra mutants and IL-15 mutants that were capable of binding IL-15 and IL-l5Ra.
Thus, the specification does not provide an adequate written description of the genus of IL-l5Ra mutants and IL-15 mutants that were capable of binding IL-15 and IL-l5Ra that is required to practice the claimed invention. Applicants have not described the genus of autoantibodies sufficiently to show they had possession of the claimed genus. Since the disclosure fails to provide sufficient relevant identifying characteristics, and because the genus is highly variant, 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.
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.
Claims 22-26, 29, 31-34 and 36-38 are rejected under 35 U.S.C. 103 as being unpatentable over Krah et al (New Biotechnology 39:167-173, 2017, IDS) and Baurin et al (US 2014/0011238, published January 9, 2014) in view of Bernett et al (WO 2019/006472, published January 3, 2019, IDS) and Crossdale et al (WO 2015/091738, published June 25, 2015, IDS) in further view of Cox (US 2003/0162949, published August 28, 2003) and Waldmann et al (2007/0160578, published July 12, 2007).
Krah provides an overview of known solutions to ensure cognate L and H chain
assembly for bispecific antibodies (page 168, 2nd column to page 171, 2nd column; Figures 2, 3). Krah discloses that one antibody Fab arm uses TCR Cα and Cβ domains to replace CH1 and CL1 to ensure cognate pairing (Figure 3B). Krah disclose methods for improving heavy chain heterodimerisation (ie the generation of desired heterodimers), including C region knobs-into-holes technique (Id). Krah discloses the knobs-into-holes mutations, FC-A chain-T366W and FC-B chain-T366S/L368A,N407V (page 169, 1st column). Krah further discloses modifications of the VH and VL domains (page 170, 2nd column; Figure 3).
Baurin discloses an bispecific antibody binding protein comprising four polypeptide chains that form four antigen binding sites comprising different configurations of VH1, VH2, VL1, VH1, CL, CH1 and CH2 as well as intervening linkers (paragraph 24-58, 82-98, 141-163, 170-205). Baurin discloses bispecific antibodies that bind Her2 (paragraph 168).
One of ordinary skill in the art would be motivated to combine Krah and Baurin because both Krah and Baurin concern methods for optimizing correct pairing of antibody chains in bispecific antibodies.
Neither Krah nor Baurin disclose the substitution of the CH1 and CL chains with IL-15 and IL-15Ra sequences.
Bernett disclose bifunctional heterodimeric Fc fusion proteins that include an IL-15/IL-I5Ra complex (paragraph 284-294; Figures 16, 57, 80). Bernett discloses IL-15 or IL-15Ra, is attached to an Fc domain (paragraph 232, 233)
One of ordinary skill in the art would have been motivated to apply Bernett’s IL-15/IL-I5Ra complex for use in bispecific antibodies to Krah and Baurin engineered bispecific antibodies because Krah, Baurin and Bernett disclose engineered bispecific antibodies to optimize pairings between different immunoglobulin chains. One of ordinary skill in the art would have been motivated to substitute the IL-15 and IL-I5Ra pairings of Bernett for the TCR Cα and Cβ domains of Krah because both pairings have been disclosed to replace CH1 and CL1 domains in bispecific antibodies.
Neither Krah, Baurin nor Bernett disclose a bispecific antibody that binds two Her2 epitopes.
Croasdale discloses bispecific antibodies that comprise trastuzumab and pertuzumab (example 2; Tables 32- 33). Croasdale disclose the treatment of cancer with the bispecific antibody (page 67 line 15 to page 68 line 5; example 10).
One of ordinary skill in the art would have been motivated to apply Croasdale bispecific antibodies that comprise trastuzumab and pertuzumab to Krah, Baurin and Bernett engineered bispecific antibody comprising IL-15 and IL-I5Ra because both Croasdale and Baurin discloses bispecific antibodies that bind Her2. It would have been prima facie obvious to combine Krah, Baurin and Bernett engineered bispecific antibody comprising IL-15 and IL-I5Ra with Croasdale bispecific antibodies that comprise trastuzumab and pertuzumab to have a bispecific antibody, which comprises: a) a first antibody that specifically binds to a first antigen; and b) a second antibody that specifically binds to a second antigen; wherein, the first antibody comprises two polypeptide chains: chain 1 and chain 2; the second antibody comprises two polypeptide chains: chain 3 and chain 4, wherein chain 3 is the heavy chain of the second antibody, and chain 4 is the light chain of the second antibody; and the first antibody and the second antibody are polymerized through chains 2 and 3; wherein the first antibody comprises IL15 and IL15Ra, and the IL15 and IL15Ra are located on two polypeptide chains of the first antibody, respectively, and are capable of forming an IL15/IL15Ra complex; and the constant domains CH1 and CL of the first antibody are replaced by the IL 15 and IL l 5Ra; the IL15 comprises the wild-type capable of binding to IL15Ra thereof, and the IL15Ra comprises the wild-type.
One of ordinary skill in the art would have had a reasonable expectation of success because as demonstrated by Krah, Baurin and Bernett, engineering bispecific antibody comprising IL-15 and IL-I5Ra with Croasdale engineering bispecific antibodies was well known in the art.
With regards to claim 32 Cox discloses the amino acid sequence for IL-15 (SEQ ID NO:1) while Waldmann disclose the amino acid sequence for IL15Ra (SEQ ID NO:4) (see sequence comparisons below).
With regards to claim 34 the limitation “preferably, wherein the bispecific antibody is obtained by expressing fusion sequences of SEQ ID No: 10, SEQ ID No: 11, SEQ ID No: 13, SEQ ID No: 12 has been interpreted as not being required.
SEQ ID NO:1
Sequence 20, US/10298148
Publication No. US20030171284A1
GENERAL INFORMATION
APPLICANT: Cox III, George N
APPLICANT: Bolder Biotechnology, Inc.
TITLE OF INVENTION: Derivatives of Growth Hormone and Related Proteins
FILE REFERENCE: 4152-1-PUS
CURRENT APPLICATION NUMBER: US/10/298,148
CURRENT FILING DATE: 2002-11-15
PRIOR APPLICATION NUMBER: US/09/462,941
PRIOR FILING DATE: 2000-01-14
PRIOR APPLICATION NUMBER: 60/052,516
PRIOR FILING DATE: 1997-07-14
NUMBER OF SEQ ID NOS: 41
SEQ ID NO 20
LENGTH: 114
TYPE: PRT
ORGANISM: Homo sapiens
Query Match 100.0%; Score 581; Length 114;
Best Local Similarity 100.0%;
Matches 114; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIH 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIH 60
Qy 61 DTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS 114
||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS 114
SEQ ID NO:4
US-11-639-877-6
(NOTE: this sequence has 806 duplicates in the database searched)
Sequence 6, US/11639877
GENERAL INFORMATION
APPLICANT: The Government of the United States of America as
APPLICANT: Represented by the Secretary of the Department of Health and Human Services
APPLICANT: Waldmann, Thomas
APPLICANT: Dubois, Sigrid
APPLICANT: Mueller, Juergen
APPLICANT: Zhang, Meili
APPLICANT: Patel, Hiral
TITLE OF INVENTION: EXPANSION OF NATURAL KILLER AND CD8 T-CELLS WITH IL 15R/LIGAND
TITLE OF INVENTION: ACTIVATOR COMPLEXES
FILE REFERENCE: 4239-71960-02
CURRENT APPLICATION NUMBER: US/11/639,877
CURRENT FILING DATE: 2006-12-14
PRIOR APPLICATION NUMBER: 60/750,639
PRIOR FILING DATE: 2005-12-15
NUMBER OF SEQ ID NOS: 29
SEQ ID NO 6
LENGTH: 65
TYPE: PRT
ORGANISM: Homo sapiens
Query Match 100.0%; Score 356; Length 65;
Best Local Similarity 100.0%;
Matches 65; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLTECVLNKATNVAHWTTPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLTECVLNKATNVAHWTTPS 60
Qy 61 LKCIR 65
|||||
Db 61 LKCIR 65
Summary
No claims allowed.
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