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 of the invention of Group I, drawn to a recombinant protein comprising a masking polypeptide linked to a single domain antibody or antigen-binding fragment thereof via a protease-sensitive linker in the reply filed on 01/07/2026 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 further elects the species as follows: 1) a recombinant protein; 2) a masking peptide comprising an amino acid sequence at least 80% identical to SEQ ID NO: 3; 3) an sdAb that binds to CD3; and 4) a recombinant protein comprising an amino acid sequence at least 80% identical to SEQ ID NO: 6. Newly added claim 27 is directed to the elected recombinant protein species. Newly added claims 28 and 29 are directed to the non-elected species (i.e. CSAN).
Thus, claims 5-7, 12-15, 19, 20-22, 24-26, 28, and 29 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 01/07/2026.
Claims 1-4, 8-11, 16-18, 23, and 27 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 4, 16, 17, and 18 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.
Claim 4 recites that the recombinant protein comprises an amino acid sequence at least 80% identical to SEQ ID NO: 3 (the masking polypeptide HINT1) and thus represents a partially defined structure in which at most 20% of the amino acid sequence can vary.
Claim 16 recites that the recombinant protein has at least 80% sequence identity to SEQ ID NO: 6 (elected species), which comprises the anti-CD3 sdAb of SEQ ID NO: 1, the MMP-2 cleavable peptide of SEQ ID NO: 4, and the masking polypeptide of SEQ ID NO: 3. Thus, the claimed recombinant protein represents a partially defined structure in which at most 20% of the amino acid sequence can vary across several domains, including in the CDRs of the anti-CD3 sdAb, the masking polypeptide human HINT1, and the MMP2 cleavable peptide.
Claim 17 recites that the recombinant protein comprises a DHFR2 domain sequence having at least 80% sequence identity to SEQ ID NO: 14 and thus represents a partially defined structure in which at most 20% of the amino acid sequence can vary.
Claim 18 recites that the recombinant protein has at least 80% sequence identity to SEQ ID NO: 21, which comprises the amino acid sequence of SEQ ID NO: 6 (elected species) in addition to the DHFR2 domain sequence of SEQ ID NO: 14. Thus, the claimed recombinant protein can vary in at most 20% of the amino acid sequence across several domains, including in the CDRs of the anti-CD3 sdAb, the masking polypeptide human HINT1, the MMP2 cleavable peptide, and DHFR2 domain.
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.
Claim 4 recites that the recombinant protein comprises an amino acid sequence at least 80% identical to SEQ ID NO: 3 (the masking polypeptide HINT1) and thus represents a partially defined structure in which at most 20% of the amino acid sequence can vary. Such variation can occur, for example, by amino acid substitution, deletion, or insertion. However, there is no guidance provided in the specification about which specific amino acids mutations can made in the masking polypeptide HINT1 (SEQ ID NO: 3) such that it retains the functional property of reducing binding affinity of the single domain antibody (sdAb) to its target antigen commensurate in scope of the claims.
Claim 16 recites that the recombinant protein has at least 80% sequence identity to SEQ ID NO: 6 (elected species). The recombinant protein represented by SEQ ID NO: 6 comprises the masking polypeptide HINT1 (SEQ ID NO: 3), an anti-CD3 sdAB (SEQ ID NO: 1), and an MMP2 cleavable peptide (SEQ ID NO: 4) (see Table 1 of Specification). As presently written, the recombinant protein can vary in at most 20% of the amino acid sequence and thus comprise random, undefined mutations across multiple domains, including the masking polypeptide, anti-CD3 sdAb, and MMP-2 cleavable peptide. However, there is no guidance provided in the specification about which specific amino acids mutations can made in the recombinant protein without disrupting masking activity of HINT1, cleavage of the protein by an MMP-2 protease, or binding affinity to CD3. Indeed, it is well-known in the art that amino acid substitutions in the antibody in the CDR domains, in particular, can negatively impact binding activity (see, e.g. Piche-Nicholas et al, see in particular, Abstract; Colman, see entire document particularly Page 33, Col. 2; and Rudikoff et al, see Abstract). The level of skill and knowledge in the art is such that one of ordinary skill would not be able to readily identify without further testing which amino acid mutations can be made in the CDR sequences of sdAb such that binding affinity to CD3 is retained.
Claim 17 recites that recombinant protein further comprises a DHFR2 domain sequence having at least 80% sequence identity to SEQ ID NO: 14 and thus represents a partially defined structure in which at most 20% of the amino acid sequence can vary. The DHFR2 domain is capable of dimerization to form multimeric structures in the presence of bis-methotrexate (see Page 19 of the Specification). However, there is no guidance provided in the specification regarding specific mutations that can be made in the DHFR2 domain of the claimed recombinant proteins without disrupting the ability of the recombinant protein to form multimeric structures.
Similarly, claim 18 recites that the recombinant protein has at least 80% sequence identity to SEQ ID NO: 21, which comprises the amino acid sequence of SEQ ID NO: 6 (elected species) in addition to the DHFR2 domain sequence of SEQ ID NO: 14. Thus, the claimed recombinant protein can vary in at most 20% of the amino acid sequence across several domains, including in the CDRs of the anti-CD3 sdAb, the masking polypeptide human HINT1, the MMP2 cleavable peptide, and DHFR2 domain. However, there is no guidance provided in the specification about which specific amino acids mutations can made in the recombinant protein without disrupting masking activity of HINT1, cleavage of the protein by an MMP-2 protease, binding affinity to CD3, or the ability of the DHFR2 domain to form multimeric structures.
Therefore, the claimed genus of recombinant proteins, masking polypeptides, and DHFR2 domain lacks adequate written description because there does not appear to be any correlation between the structure of the recombinant proteins, masking polypeptides, and DHFR2 molecules having undefined amino acid mutations and the ability to retain functional activity. 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 recombinant proteins, masking polypeptides, and DHFR2 domains having undefined amino acid mutations at the time the instant application was filed.
Scope of Enablement
Claims 4, 16, 17, and 18 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 a HINT1 masking polypeptide (SEQ ID NO: 3), recombinant protein (SEQ ID NO: 6 or 21), and dihydrofolate reductase (DHFR2) (SEQ ID NO: 14) that are fully-defined by SEQ ID NO, does not reasonably provide enablement for HINT1 masking polypeptide, recombinant protein, and DHFR2 domain variants comprising undefined amino acid mutations, wherein the specification provides no data or technical guidance demonstrating that such variants retain functional activity. 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 masked single domain antibodies (sdabs) comprising a masking polypeptide linked to a sdAb via a protease-sensitive linker (see Summary of the Invention).
Claim 4 is broadly drawn to a recombinant protein that comprises an amino acid sequence at least 80% identical to SEQ ID NO: 3 (the masking polypeptide human HINT1) and thus represents a partially defined structure in which at most 20% of the amino acid sequence can vary.
Claim 16 is broadly drawn to a recombinant protein having at least 80% sequence identity to SEQ ID NO: 6 (elected species) and thus represents a partially defined structure in which at most 20% of the amino acid sequence can vary, including in the CDRs present in the anti-CD3 sdAb, the masking polypeptide human HINT1, and the MMP2 cleavable peptide present in the recombinant protein.
Claim 17 is broadly drawn to a recombinant protein comprising a DHFR2 domain sequence having at least 80% sequence identity to SEQ ID NO: 14 and thus represents a partially defined structure in which at most 20% of the amino acid sequence can vary.
Claim 18 is broadly drawn to a recombinant protein comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 21, which comprises the amino acid sequence of SEQ ID NO: 6 (elected species) in addition to the DHFR2 domain sequence of SEQ ID NO: 14. Thus, the claimed recombinant protein can vary in at most 20% of the amino acid sequence across several domains, including in the CDRs of the anti-CD3 sdAb, the masking polypeptide human HINT1, the MMP2 cleavable peptide, and DHFR2 domain.
The specification teaches the development of a masked anti-CD3-DHFR2 fusion protein containing an anti-CD3 sdAb. To mask the anti-CD3 sdAb, human histidine triad nucleotide binding protein 1 (hHINT1) was fused to the N-terminus of the sdAb via an MMP-2 sensitive linker to serve as a steric mask. (Example 1). The recombinant protein represented by SEQ ID NO: 6 comprises hHINT1 (SEQ ID NO:3) fused to an anti-CD3 sdAb (SEQ ID NO: 1) via an MMP-2 sensitive linker (SEQ ID NO: 4). The recombinant protein of SEQ ID NO: 21 further comprises a DHFR2 domain of SEQ ID NO: 14 in addition to the amino acid sequence of SEQ ID NO: 6 (see Table 1). As presently written, the claims thus encompass recombinant proteins comprising mutations in different domains, including the masking polypeptide HINT1, the anti-CD3 sdAb, MMP-2 cleavable linker, or DHFR2 domain capable of dimerization to form multimeric structures (see Page 19 of the Specification). However, neither the specification nor prior art provides sufficient guidance regarding which mutations can be introduced in these domains while preserving the required functional properties. The effect of mutations within these domains is not readily predictable, and such mutations may disrupt essential functions such as masking activity of HINT1, cleavage by an MMP-2 protease, the ability of DHFR2 domain to dimerize and form multimeric complexes, or binding affinity to CD3. Indeed, it is well-known in the art that amino acid mutations in the CDR domains of an antibody can negatively impact binding activity (see, e.g. Piche-Nicholas et al, see in particular, Abstract; Colman, see entire document particularly Page 33, Col. 2; and Rudikoff et al, see Abstract). As such, amino acid mutations in the anti-CD3 sdAb domain present in the recombinant protein can disrupt the ability of the recombinant protein to target CD3.
A person of ordinary skill in the art at the time of filing would have had experience in protein engineering, including mutagenesis and screening techniques. Even at this high level of skill, however, the impact of random amino acid mutations on the functional activity of various domains in the claimed recombinant proteins (i.e. masking polypeptide, anti-CD3 sdAb, MMP-2 cleavable peptide, or DHFR2 domain) cannot be readily predicted without additional testing. 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 substantial experimentation across the full scope of the claimed genus especially given that there is no guidance provided in the specification or prior art on which amino acid mutations can be made in the masking polypeptide, MMP2 cleavable peptide, anti-CD3 sdAb, or DHFR2 domain of a recombinant protein such that it retains the required functional property of each domain.
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 1-3, 8-11, 23, and 27 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C.102(a)(2) as being anticipated by Irving et al (US20160194399A1), hereinafter Irving.
Irving discloses an activatable antibody that in an activated state binds the epsilon chain of CD3 (CD3ε), wherein the activatable antibody comprises an antibody or an antigen binding fragment (AB) thereof— such as a single domain heavy chain antibody— that specifically binds to CD3ε; a masking moiety (MM) that inhibits the binding of the antibody to CD3ε when the activatable antibody is in an un-cleaved state; and a cleavable moiety (CM)—a polypeptide substrate for a protease—coupled to the antibody (Abstract; Para. 0020, 0055, and 0059; Claims 11 and 20). The MM can sterically inhibit the binding of the AB to the target (Para. 0406). The protease is produced by a tumor that is in proximity to cells that express CD3ε in a tissue and/or produced by a tumor that is co-localized with CD3ε in a tissue, wherein the protease cleaves the cleavable moiety in the activatable antibody when the activatable antibody is exposed to the protease (Para. 0020 and 0054; Claim 17). In the un-cleaved state, the activatable antibody has the structural arrangement from N-terminus to C-terminus as follows: MM-CM-AB or AB-CM-MM (Para. 0056). The protease-sensitive cleavable moiety comprises the amino acid sequence of SEQ ID NO: 85 (SGGPLGVR) (Para. 0097), wherein the protease is a matrix metalloproteinase (Para. 0261). The amino acid sequence of SEQ ID NO: 85 fully comprises the amino acid sequence of SEQ ID NO: 4 (GPLGVR) recited in the instant claims. Further disclosed is a pharmaceutical composition comprising the activatable antibody and a carrier (Para. 0533 and Claims 40 and 41).
Thus, Irving meets the limitations of claims 1-3, 8-11, 23, and 27.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Irving, as applied to claims 1-3, 8-11, 23, and 27 above, and further in view of Fegan et al (Fegan, Adrian et al. “Chemically self-assembled antibody nanostructures as potential drug carriers.” Molecular pharmaceutics vol. 9,11 (2012): 3218-27. doi:10.1021/mp300303k), hereinafter Fegan and Hackel et al (US20180251524A1), hereinafter Hackel.
The teachings of Irving have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the activatable antibody further comprises DHFR2 of SEQ ID NO: 14.
However, Fegan teaches dimeric dihydrofolate reductase (DHFR2) fused to an antibody (e.g. an anti-CD3 scFv) spontaneously self-assembles into multimeric structures upon the addition of the chemical dimerizer bis-methotrexate (bis-MTX), allowing for the creation of controlled valency structures which can be utilized for delivery of therapeutic agents. Therefore, an antibody conjugated to DHFR2 represents a precursor construct that can be used to make multimeric structures in the presence of a chemical dimerizer (Abstract and Introduction).
Hacklel further teaches the use of a DHFR2 polypeptide having the amino acid sequence set forth in SEQ ID NO: 14 of the instant claims in fusion proteins (e.g. in SEQ ID NO: 59) to facilitate oligomerization of the proteins into multimeric structures (Para. 0177-0178 and 0449).
It would have been obvious to one of ordinary skill in the art to modify the activatable anti-CD3 antibody of Irving such that it is further conjugated to DHFR2 of SEQ ID NO: 14. One of ordinary skill in the art would have been motivated to do so since an antibody- DHFR2 represents a precursor construct that can form multimeric structures in the presence of a chemical dimerizer, such as bis-methotrexate; in turn, these multimeric structures can be used for controlled valency and delivery of therapeutic agents as taught by Fegan. Additionally, it would have been obvious to artisans to substitute the DHFR2 disclosed by Fegan with that disclosed by Hackel having the amino acid sequence of SEQ ID NO: 14 set forth in the instant claims because both have the same function and can be used for the same purpose. An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213USPQ 532 (CCPA 1982).Therefore, one of ordinary skill in the art would have been motivated to conjugate the activatable anti-CD3 antibody (i.e. masked anti-CD3 antibody) to DHFR2 of SEQ ID NO: 14. in order to make a precursor construct that can form in the presence of a chemical dimerizer multimeric structures useful for controlled valency and targeted delivery of the therapeutic agent.
Conclusion
No claims are allowable.
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/LIA E TAYLOR/ Examiner, Art Unit 1641
/MISOOK YU/ Supervisory Patent Examiner, Art Unit 1641