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/Restrictions
Applicant’s election without traverse of the invention of Group I, drawn to an anti-cleaved iCaspase substrate antibody, in the reply filed on 02/13/2026 is acknowledged. Applicant further elects, without traverse, an anti-iCaspase antibody species having the VH and VL chains of SEQ ID NOs: 1 and 2.
Claims 17, 18, 19-23, 25, 27, 28, 29, 32, and 35 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 02/13/2026.
The elected anti-iCaspase antibody was found to be free of the prior art and thus the election of species requirement for the anti-iCaspase antibody has been withdrawn.
Claims 1, 11-13, 15, 16, 36, and 38-41 are examined on the merits in the present Office Action.
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.
Written Description
Claims 1, 11-13, 15, 16, 36, and 38-41 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1 and 36 fail to recite the amino acid sequences of six non-degenerate CDRs for the genus of antibodies that bind a cleaved inflammatory caspase (iCaspase) substrate, wherein the antibody specifically binds to a peptide comprising the amino acid sequence P4-P3-P2-D at the C-terminus of the peptide but does not bind to peptides having the amino acid sequence of D-X-X-D or E-X-X-D at the C-terminus.
Further, claims 1, 11, and 36 do not identify P4, P3, or P2 present in the peptide that is targeted by the anti-iCaspase antibody. Per the specification, caspases in general tolerate sequence diversity at positions P3 and P2. However, iCaspases in particular prefer substrates with a hydrophobic residue at P4. While the claim excludes P4 from being aspartate (D), P4 can be any other amino acid, including a non-hydrophobic amino acid, in the absence of a limiting definition.
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 (MPEP 2163).
In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin [e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, 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.”
The court has further stated that “Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Id. at 1566, 43 USPQ2d at 1404 (quoting at 1171, 25 USPQ2d at 1606). Also see (CAFC 2002). Enzo-Biochem v. Gen-Probe Fiers, 984 F.2d 01-1230.
Claims 1 and 36 are broadly drawn to antibodies and kits comprising said antibodies that bind cleaved inflammatory caspase (iCaspase) substrates having the motif P4-P3-P2-D at the C-terminus of the peptide but do not bind to peptides having the motifs D-X-X-D or E-X-X-D.
It is well-known in the art that, in order to bind antigen, a conventional antibody or antigen-binding fragment must have six complementarity defining regions (CDRs) (Janeway, see selection, in particular section 3-6). Because CDRs from both VH and VL domains contribute to the antigen-binding site, it is the combination of the heavy and the light chain, and not either alone, that determines the final antigen specificity. As presently written, however, claims 1 and 36 do not recite the amino acid sequences of six non-degenerate CDRs for the genus of “antibodies that bind a cleaved inflammatory caspase (iCaspase) substrate, wherein the antibody specifically binds to a peptide comprising the amino acid sequence P4-P3-P2-D at the C-terminus of the peptide but does not bind to peptides having the amino acid sequence of D-X-X-D or E-X-X-D at the C-terminus.. While Applicant has provided examples of antibodies that can target the iCaspase substrates having the claimed motif but not to peptides having the D-X-X-D or E-X-X-D motif, such disclosure does not adequately represent the structural diversity of the claimed genus of antibodies having the functional properties recited in the claims. Without further guidance, artisans would have to engage in additional, unpredictable basic science research to identify antibodies that bind a cleaved iCaspase substrates having the motif P4-P3-P2-D at the C-terminus but not to peptides having the motifs D-X-X-D or E-X-X-D.
Further, claims 1, 11, and 36 do not identify P4, P3, or P2 present in the peptide that is targeted by the anti-iCaspase antibody. Per the specification, caspases in general tolerate sequence diversity at positions P3 and P2. However, iCaspases in particular prefer substrates with a hydrophobic residue at P4 (Para. 0097). While the claim excludes P4 from being aspartate (D), P4 can be virtually any other amino acid, including a hydrophilic amino acid, in the absence of a limiting definition. As such, the claims (and any claim dependent therefrom) encompass antibodies that bind to the motifs that are not present in iCaspase substrates (i.e. P4-P3-P2-D having a non-hydrophobic amino acid). In other words, claims 1, 11 and 36 encompass antibodies not correlated with the functional property of binding to an iCaspase substrate. Claims 11-13, 15, 16, and 38-41, which depend directly or indirectly from claim 11, do not cure the deficiencies of claim 11 and are thus also rejected.
Therefore, the claimed genus of antibodies thereof lacks adequate written description because there does not appear to be any correlation between the structure of the claimed antibodies and the function of binding to iCaspase substrates having the motif P3-P3-P2-D at the C-terminus but not to peptides having the motifs D-X-X-D or E-X-X-D. Thus, one of ordinary skill in the art would reasonably conclude that the applicant was not in possession of the full breadth of the claimed genus of antibodies at the time the instant application was filed.
Scope of Enablement
Claims 1, 11-13, 15, 16, 36, and 38-41 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 an antibody that binds to an iCaspase substrate having the motif P4-P3-P2-D, wherein P4 is a hydrophobic amino acid, does not reasonably provide enablement for anti-iCaspase antibodies that bind to substrates having a non-hydrophobic amino acid at P4. 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 or use the invention commensurate in scope with these claims.
The nature of the invention relates to antibodies that bind to cleaved inflammatory caspase (iCaspase) substrates and methods of use (see Field of Invention, Para. 0003).
Claims 1, 11, and 36 are broadly drawn to antibodies and kits comprising said antibodies that bind cleaved inflammatory caspase (iCaspase) substrates having the motif P4-P3-P2-D at the C-terminus of the peptide but do not bind to peptides having the motifs D-X-X-D or E-X-X-D.
The specification teaches the generation of both monoclonal and polyclonal antibodies that target iCaspase substrates having W/YxxD and I/LxxD motifs, wherein W/Y/I are at position P4 and D is at position P4. (Examples 1 and 2). In particular, the monoclonal antibody (mAb) clones CJ2 and CJ11 (presently recited in the instant claims) showed the desired P1 and P4 specificity and exhibited similar binding to both WxxD and IxxD pools. Further, the mAbs showed no binding to the control peptides having apoptotic caspase motif DxxD or W/IxxD capped with an amide (W/I-xxD-NH2) (Example 2, Para. 0203). Both CJ11 and CJ2 only tolerated Asp (D) at P1 and did not show recovery of any peptide with a P4 Asp (D). It was concluded that the two mAbs CJ2 and CJ11 have broad recognition for known iCasp substrates that require both a free C-terminus Asp (D) at P1 and a hydrophobic residue at P4 for efficient binding. (Example 2, Para. 0205). However, the specification does not provide evidence that 1) the CJ11 and CJ2 antibodies can bind to substrates having a non-hydrophobic amino acid at P4 or 2) antibodies that bind to a motif having a non-hydrophobic residue at P4 are capable of targeting an iCaspase substrate. Further, there does not appear to be any guidance provided in the specification for identifying anti-iCaspase antibodies that target substrates having a non-hydrophobic residue at P4.
The prior art, as referenced in the specification, teaches that caspases typically cleave substrates having the motif P4-P3-P2-P1, wherein P1 is Asp (D). In general, caspases tolerate sequence diversity at positions P2 and P3. At position 4 (P4), the apoptotic caspases (e.g., caspase-3, -6, and -7) prefer substrates with an aspartic acid (e.g. D-X-X-D). In contrast, the inflammatory caspases (iCaspases) prefer substrates with a hydrophobic P4 residue (e.g. W/I-X-X-D) (Para. 0097 of the Specification; Kang et al, see Abstract and Introduction; Thornberry et al, see Abstract, Introduction, and Figures 2-3). The prior art does not appear to teach that inflammatory caspase substrates comprise a motif having a non-hydrophobic amino acid residue at P4. As such, artisans would not reasonably expect anti-iCaspase antibodies to bind to a peptide having the motif P4-P3-P2-P1, wherein P4 is a non-hydrophobic amino acid. It is not predictable that antibodies that bind peptides comprising a motif of the form P4-P3-P2-D wherein D is a non-hydrophobic residue will bind in a comparable manner to peptide in which P4 is a hydrophobic residue. Substitution of a hydrophobic residue for a non-hydrophobic residue at position P4 can significantly alter binding affinity of the antibody. Indeed, as demonstrated in Examples 2 and 3 of the specification, the anti-iCaspase antibodies CJ2 and CJ11 bind to motifs having W/I-X-X-D but not to those having D-X-X-D.
A person of ordinary skill in the art at the time of filing would have had experience in antibody engineering, including screening techniques. Even at this high level of skill, however, it cannot be readily predicted without additional testing if an antibody that binds to a peptide having the motif P4-P3-P3-D wherein P4 is a non-hydrophobic residue can be used to target iCaspase substrates. In Amgen Inc. v. Sanofi, Aventisub LLC, 987 F.3d 1080 (Fed. Cir. 2021), which the Supreme Court affirmed, the Federal Circuit relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Id. at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement (MPEP 2164.06). Thus, the level of skill does not obviate the need for additional experimentation across the full scope of the claimed genus. Claims 11-13, 15, 16, and 38-41, which depend directly or indirectly from claim 11, do not cure the deficiencies of claim 11 and are thus also rejected.
Therefore, the specification is not enabling over the full scope of the claims.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1 and 36 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Comb et al (US20120208985A1), hereinafter Comb.
Comb discloses antibodies that specifically bind to a cleaved caspase motif (Para. 0018) having the sequence XND, wherein D is aspartate, X is any amino acid, and N is greater than or equal to 1. For example, the motif comprises the sequences XXXD, wherein X is any amino acid and D is aspartate. In more particular embodiments, the motif comprises a sequence selected from the group consisting of IETD, LESD, LETD, METD, and VETD (Para. 0022). As such, the caspase substrate can comprise a hydrophobic residue (e.g. Ile, Leu, Met, or Val) at position P4. Per the instant specification, iCaspases prefer substrates with a hydrophobic residue at P4. Hence, the antibodies disclosed by Comb can bind to inflammatory caspase (iCaspase) substrates. Following cleavage by a caspase, one of the two fragments of a protein/peptide will have the following sequence: (N terminus) . . . XXXXXXXXD (C terminus), wherein XXXXXXXXD is the caspase motif (Para. 0239). Thus, the antibodies disclosed by Combs necessarily target an iCaspase substrate comprising the XXXD (e.g. IETD) motif at the C-terminus of the peptide. While the reference does not explicitly disclose a “kit” or “instructions of use”, these limitations do not impart structural distinction over the prior art. A kit merely refers to a combination or grouping of components. The claim does not recite any additional structural features of the kit beyond the anti-iCaspase antibody. Therefore, the disclosure of an antibody that binds to an iCaspase substrate having the amino acid sequence IETD, LESD, LETD, METD, or VETD (wherein P4 is a hydrophobic amino acid) satisfies this limitation. The “instructions for use” are non-structural and directed to the intended use of the claimed composition. It is taught that the antibodies disclosed can be used as a reagent in specific detection methods (e.g. profiling genome wide changes in protein levels) (Para. 0014). Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004) (MPEP 2112.01). Moreover, statements of intended use do not distinguish over the prior art where the prior art teaches the same structure capable of performing the intended use (MPEP 2111.02).
Thus, Comb meets the limitations of instant claims 1 and 36.
Conclusion
No claims are allowable.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641