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
Newly added claims 35 and 36 are directed to a non-elected species (recombinant proteins targeting PSMA). Thus, claims 35 and 36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim.
Response to Amendment
Applicant’s remarks and amendments to the claims filed 06/16/2026 have been acknowledged. Claims 1, 4, 10, 15, and 16-18 have been amended. Claims 2, 5-7, 21, 25, and 28 have been canceled. Claims 30-36 are newly added. The claim amendments overcome rejections under 35 USC 102 and 103 previously set forth in the Non-Final Rejection of 03/16/2026.
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, 3, 4, 8-11, 16, 17, 18, 23, 27, 30, 31, and 32 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 1 recites a recombinant protein comprising a masking polypeptide having at least 95% identical to SEQ ID NO: 3 (the masking polypeptide HINT1) and thus represents a partially defined structure in which at most 5% of the amino acid sequence can vary. Similarly, claims 31 and 32 recite recombinant proteins wherein the masking polypeptides are at least 97% or 98% identical to SEQ ID NO: 3, respectively and thus also encompass structures in which at most 3% or 2% of the amino acid sequence can vary. Claims 3, 4, 8-11, 23, 27, 30, 31, and 32 depend from claim 1 but do not cure the deficiencies of claim 1 and are thus also rejected.
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 1 recites a recombinant protein comprising a masking polypeptide having at least 95% identical to SEQ ID NO: 3 (the masking polypeptide HINT1) and thus represents a partially defined structure in which at most 5% of the amino acid sequence can vary. Similarly, claims 31 and 32 recite recombinant proteins wherein the masking polypeptides are at least 97% or 98% identical to SEQ ID NO: 3, respectively and thus also encompass structures in which at most 3% or 2% 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. Claims 3, 4, 8-11, 23, 27, 30, 31, and 32 depend from claim 1 but do not cure the deficiencies of claim 1 and are thus also rejected.
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 1, 3, 4, 8-11, 16, 17, 18, 23, 27, 30, 31, and 32 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 1 recites a recombinant protein comprising a masking polypeptide having at least 95% identical to SEQ ID NO: 3 (the masking polypeptide HINT1) and thus represents a partially defined structure in which at most 5% of the amino acid sequence can vary. Similarly, claims 31 and 32 recite recombinant proteins wherein the masking polypeptides are at least 97% or 98% identical to SEQ ID NO: 3, respectively and thus also encompass structures in which at most 3% or 2% 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.
Response to Arguments
Applicant's arguments filed 06/16/2026 have been fully considered but they are not persuasive with respect to rejections under 35 USC 112(a) written description and enablement.
With respect to 35 USC 112(a) rejections, Applicant argues the following:
Applicant respectfully notes that instant application established that hHINT1 based masking polypeptide successfully reduced different single domain antibodies (sdAbs) from binding their targets. For example, hHINT1 based masking polypeptide reduced anti-CD3 sdAb binding to its target and anti-PSMA sdAb binding to its target as shown in Examples 1-2, e.g., page 61 lines 7-11; page 66 lines 13-29 of the substitute specification submitted on 09/06/2023; Fig. 15 and Fig. 19.
Applicant further notes that at least two hHINT1 based masking polypeptides of different lengths, SEQ ID NO:3 and SEQ ID NO:31, are disclosed in the application (see Table 1 on page 28). Furthermore, two additional hHINT1 sequences (NCBI accession NOs: P49773.2 and 5IPEA) are also disclosed on page 8 line 4 of the substitute specification. Based on the disclosure of the instant application, one skilled in the art would reasonably understand that applicant had possession of the instantly claimed invention.
As noted above, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics, i.e., complete or partial structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structures, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. M.P.E.P. §2163.
Therefore, since the instant application showed a correlation between steric masking function and the function determining structure (hHINT1 sequence that is linked to the N- terminus of sdAb), and that specific identifying structures of 95% sequence identity to hHINT1 sequence are sufficiently recited, Applicant respectfully submits that the written description requirement is satisfied for the instantly claimed invention.
Regarding claims 16-18, at least two exemplary DHFR2 sequences (SEQ ID NO:14, or 37) were disclosed in the application. In addition, since certain sdAb variants having minor changes in framework regions and/or CDR regions may still bind its target, and the instant application showed successful steric masking function for very different single domain antibodies (sdAbs) (e.g., anti-CD3 and anti-PMSA sdAbs (SEQ ID NO: 1 vs 2) having less than 85% sequence identity), Applicant respectfully submits that the written description requirement is satisfied for the amended claims 16-18.
In summary, the written description requirement is satisfied for claim 1 and its dependencies
Applicant respectfully submits that the enablement requirement is satisfied at least for the reasons and/or amendments presented above. Moreover, in addition to the anti-CD3 and anti-PMSA sdAbs mentioned above, hHINT1 based masking polypeptide also successfully reduces bindings of anti-EGFR sdAb, anti-TCR sdAb, and anti-CD 16 sdAb to their respective targets, evidencing the broad, universal applicability of hHINT1 mask in instantly claimed invention. See post-filing references included in the IDS submitted on 01/09/2026 (e.g., KULKARNI, et al., "Abstract 6720: HINT1 steric masked, protease-activatable bispecific protein nanorings direct human T and NK cells to eradicate EGFR* solid tumors", Cancer Research 15 March 2024; 84 (6_Supplement): https://doi.org/10.1158/1538-7445.AM2024-6720 (2024); and KULKARNI, et al., "Protease-Activatable Nanorings for Selective Redirection of Immune Cells to Combat Solid Tumors", Masonic Cancer Center Symposium - Abstract, Minneapolis, MN, 1 page (2023)). In summary, the enablement requirement is satisfied for instantly claimed invention. Reconsideration and withdrawal of the rejection is appropriate and respectfully requested.
In response to Applicant’s arguments, the Examiner notes that while the specification identifies two HINT1 variants (SEQ ID NOs: 3 and 31) and refers to refers to known HINT1 sequences (NCBI accession no: P49773.2 and 5IPEA), such disclosure is not representative of the genus of HINT1 variants encompassed by the claims having at least 95%, 97%, or 98% identity to SEQ ID NO: 3. The claims do not restrict the location, type, or number of amino acid mutations that can be made throughout the HINT1 polypeptide of SEQ ID NO: 3 beyond the 95%, 97%, 98% percent identity limitation. Thus, the claims encompass HINT1 variants beyond those identified or described in the specification. Amino acid substitutions can alter the structure and function of the polypeptide as well as protein-protein interactions (Teng et al, see entire document, in particular, Abstract and Para. 1 and 2 of Introduction )(Teng, Shaolei et al. International journal of computational biology and drug design vol. 3,4 (2010): 334-49), and thus the ability of HINT1 to function as a steric mask. However, the specification does not provide guidance identifying which amino acid mutations can be made while maintaining the structural properties necessary for HINT1 to function as a steric mask in the recombinant protein. As such, the disclosure of two particular HINT1 variants that differ in length does not demonstrate possession of the genus encompassed by the claims.
Further, the specification does not establish that HINT1 variants having amino acid mutations encompassed by the “at least 95%, 97%, or 98% identity” limitations will necessarily retain the three-dimensional structure and steric-masking properties required by the claimed recombinant protein. The disclosure of two representative HINT1 variants demonstrates, at most, that those particular variants can function as masking polypeptides. The disclosure does not establish that the full range of sequences having at least 95% (or 97% or 98%) identity to HINT1 will retain the required masking property.
Similarly, in regards to DHFR2 and the sdAb present in the recombinant protein, the disclosure of particular variants does not, by itself, does not establish full possession nor enable the full scope of the claimed genus because the claims encompass variants extending beyond those specifically disclosed. A disclosure of certain variants not establish that the skilled artisan can make any substitutions encompassed by the claimed percent-identity range. For example, even single amino acid mutations in the CDR domains of an antibody can negatively impact binding activity as discussed above; thus, amino acid mutations in the anti CD3 binding domain present in the recombinant protein can disrupt the ability of the recombinant protein to target CD3. Thus, the 35 USC 112a rejections are maintained.
Conclusion
Claims 1, 3, 4, 8-11, 16, 17, 18, 23, 27, 30, 31, and 32 are not allowable. Claims 33 and 34 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LIA TAYLOR whose telephone number is (571)272-6336. The examiner can normally be reached 8:30 - 5:00 M-F.
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, MISOOK YU can be reached at 571-272-0839. 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.
/LIA E TAYLOR/ Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
Prosecution Insights