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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/06/2026 has been entered.
Response to Amendment
Applicant’s remarks and amendments made to the claims and drawings received 03/06/2026 has been acknowledged. Claims 18, 19, and 21 have been amended. The claim amendments overcome the rejections made under 35 USC 112(a) enablement and 35 USC 112(b) previously set forth in the Final Rejection of 11/05/2025. Further, the replacement drawings overcome objections made to the specification and drawings.
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 1-8, 10, 12, 15-21, and 23-25 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 an antigen-binding fragment that binds to either FcγRIIa or platelet factor 4 (PF4) and prevents platelet activation, wherein each antigen-binding fragment comprises heavy chain variable (VH) and light chain variable (VL) regions having at least 90% sequence identity to the referenced sequences and comprising defined CDRs. As such, the scope of the claim extends beyond the specific sequences disclosed in the specification by encompassing antibodies having VH and VL framework regions that vary by up to 10% from the recited sequences. Further, there is no guidance regarding the specific amino acid mutations that can be made in the framework regions of the claimed VH and VL sequences such that the ability of the antigen-binding fragment to bind to FcyRIIa or PF4 and prevent platelet activation are retained. Claims that depend directly or indirectly from claims 1-3 (or incorporate limitations of claims 1-3) do not cure the aforementioned deficiencies and are thus also rejected.
Further, claims 4-5 encompass antigen binding fragment variants having 1, 2, or 3 amino acid substitutions in the framework region of the recited VH and VL chains. As stated above, however, there is no guidance provided in the specification about which framework residues can be varied in the VH and VL chains of the claimed antibodies without loss of binding to either FcyRIIa or PF4 and functional activity.
Similarly, claim 10 encompasses an antigen binding fragment variant having 1, 2, or 3 amino acid substitutions in the amino acid sequences of SEQ ID NO: 10 (HRU1 linked to bivalirudin) or SEQ ID NO: 11 (HRU linked to lepirudin) (see Table 1 of the Specification). Thus, the claim permits random, undefined amino acid substitutions which can occur in the framework regions of the antibody; yet, again, there is no guidance provided in the specification about which framework residues can be varied in the claimed antibodies without loss of binding to either FcyRIIa or PF4 and functional activity.
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 1-3 are directed to an antigen-binding fragment that binds to either FcγRIIa or platelet factor 4 (PF4) and prevents platelet activation, wherein each antigen-binding fragment comprising heavy chain variable (VH) and light chain variable (VL) regions having at least 90% sequence identity to the referenced sequences and comprising defined CDRs.
The specification teaches that Applicant developed antigen-binding fragments specific for FcγRIIa (HRU1 to HRU4) or platelet factor 4 (CTBR1). The clones HRU1 to HRU4 are humanized variants of mouse IV.3 monoclonal antibody whereas CTBR1 is a humanized variant of a mouse monoclonal antibody specific for human PF4 (see Para. 060-063 and Example 2). Given that the claimed antibodies comprise CDRs that are known in the prior art or derived from antibodies disclosed in the prior art, any inventive contribution of the claimed antibodies resides in their framework regions rather than in the CDR sequences themselves; however, the scope of the claims extends beyond the specific sequences disclosed in the specification by encompassing anti-FcyRIIa or PF4 antibodies having VH and VL framework regions that vary by up to 10% from the recited sequences. Such variation constitutes a substantial portion of the framework regions, yet the specification does not disclose a representative number of species within the claimed genus nor does it identify common structural features across the full scope of the claimed antibodies sufficient to demonstrate possession. Indeed, the disclosure appears to be limited to a small set of antibody clones specific for FcγRIIa (HRU1 to HRU4) or platelet factor 4 (CTBR1) and does not describe multiple framework variants spanning the breadth of the claimed ≥ 90% identity range.
Although the CDRs are often described as the primary determinants of antigen binding, it is also well-established in the art that framework residues can influence antigen binding as evidenced by partial or complete loss of binding affinity during antibody humanization and CDR grafting (Sela-Culang et al., see entire document, in particular, “FR residues” subsection under “Non-CDR Determinants That have a Role in Ag Binding”) (Sela-Culang, Inbal et al. Frontiers in immunology vol. 4 302. 8 Oct. 2013). In particular, framework residues that affect antigen binding include those that make direct contact with the antigen or are in close proximity to the CDRs and those that affect the orientation and conformation of the CDRs, impacting antigen binding indirectly (Sela-Culang et al, “FR residues” subsection, Para. 2-4). As such, the effect of framework residue mutations on antigen binding is unpredictable. However, there is no guidance provided in the specification about which framework residues can be varied in the VH and VL chains of the claimed antibodies without loss of binding to either FcyRIIa or PF4 and functional activity. 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 and evaluation antibodies having up to 10% amino acid variation in the VH and VL chains that possess the functional properties recited in the claims. Claims that depend directly or indirectly from claims 1-3 (or incorporate limitations of claims 1-3) do not cure the aforementioned deficiencies and are thus also rejected.
Claims 4-5 further encompass antigen binding fragment variants having 1, 2, or 3 amino acid substitutions in the framework region of the recited VH and VL chains. As stated above, however, there is no guidance provided in the specification about which framework residues can be varied in the VH and VL chains of the claimed antibodies without loss of binding to either FcyRIIa or PF4 and functional activity.
Similarly, claim 10 encompasses an antigen binding fragment variant having 1, 2, or 3 amino acid substitutions in the amino acid sequences of SEQ ID NO: 10 (HRU1 linked to bivalirudin) or SEQ ID NO: 11 (HRU linked to lepirudin) (see Table 1 of the Specificaiton). Thus, the claim permits random, undefined amino acid substitutions which can occur in the framework regions of the antibody; yet, again, there is no guidance provided in the specification about which framework residues can be varied in the claimed antibodies without loss of binding to either FcyRIIa or PF4 and functional activity.
Therefore, the claimed genus of antigen-binding fragments lacks adequate written description because there does not appear to be any correlation between the structure of the claimed antigen-binding fragments and the function of preventing platelet activation by blocking FcγRIIa binding on platelets, monocytes and neutrophils or neutralizing PF4. 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 antigen-binding fragments at the time the instant application was filed.
Enablement
Claims 1-8, 10, 12, 15-21, and 23-25 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The nature of the invention relates to treatment and prevention of thrombogenic diseases and disorders with antibodies that prevent platelet activation by blocking either FcyRIIa binding on platelets or neutralizing platelet factor 4 (PF4) (see Technical Field, Page 1 and Summary of Invention, Page 3).
Claims 1-3 are directed to an antigen-binding fragment binds to either FcγRIIa or platelet factor 4 (PF4) and prevents platelet activation, wherein each antigen-binding fragment comprising heavy chain variable (VH) and light chain variable (VL) regions having at least 90% sequence identity to the referenced sequences and comprising defined CDRs.
The specification teaches that Applicant developed antigen-binding fragments specific for FcγRIIa (HRU1 to HRU4) or platelet factor 4 (CTBR1). The clones HRU1 to HRU4 are humanized variants of mouse IV.3 monoclonal antibody whereas CTBR1 is a humanized variant of a mouse monoclonal antibody specific for human PF4 (see Para. 060-063 and Example 2). Given that the claimed antibodies comprise CDRs that are known in the prior art or derived from antibodies disclosed in the prior art, any inventive contribution of the claimed antibodies resides in their framework regions rather than in the CDR sequences themselves; however, as presently written, the antibodies can comprise random, undefined amino acid mutations in up to 10% of the framework regions.
As discussed earlier, framework residues can influence antigen binding as evidenced by partial or complete loss of binding affinity during antibody humanization and CDR grafting (Sela-Culang et al., see entire document, in particular, “FR residues” subsection under “Non-CDR Determinants That have a Role in Ag Binding”). In particular, framework residues that affect antigen binding include those that make direct contact with the antigen or are in close proximity to the CDRs and those that affect the orientation and conformation of the CDRs, impacting antigen binding indirectly (Sela-Culang et al, “FR residues” subsection, Para. 2-4). Indeed, a single amino acid substitution of the FR residue alanine at H71, a major determinant of the conformation of CDR loops, significantly reduces binding affinity of a mutant cB72.3m17 antibody for the TAG72 antigen likely due to a major conformational change of the CDR1/CDR2 loops (Xiang et al, see entire Document, specifically “Site Directed Mutagenesis and Affinity Constants” section). Without a reduction to practice, it is unclear how random, undefined amino acid mutations made in the framework regions would impact the ability of the claimed antibodies to bind to either FcyRIIIa or PF4. Claims that depend directly or indirectly from claims 1-3 (or incorporate limitations of claims 1-3) do not cure the aforementioned deficiencies and are thus also rejected.
Claims 4-5 further encompass antigen binding fragment variants having 1, 2, or 3 amino acid substitutions in the framework region of the recited VH and VL chains. As stated above, however, there is no guidance provided in the specification about which framework residues can be varied in the VH and VL chains of the claimed antibodies without loss of binding to either FcyRIIa or PF4 and functional activity. In the absence of further testing, artisans would not reasonably expect the claimed antibodies having up to 1, 2, or 3 undefined amino acid mutations in the framework regions to have the recited functional properties.
Similarly, claim 10 further encompasses an antigen binding fragment variant having 1, 2, or 3 amino acid substitutions in the amino acid sequences of SEQ ID NO: 10 (HRU1 linked to bivalirudin) or SEQ ID NO: 11 (HRU linked to lepirudin) (see Table 1 of the Specification). Thus, the claim permits random, undefined amino acid substitutions which can occur in the framework regions of the antibody; yet, again, there is no guidance provided in the specification about which framework residues can be varied in the claimed antibodies without loss of binding to either FcyRIIa or PF4 and functional activity. In the absence of further testing, artisans would not reasonably expect the claimed antibodies having up to 1, 2, or 3 undefined amino acid mutations in the framework regions to have the recited functional properties.
A person of ordinary skill in the art at the time of filing would have had experience in antibody engineering, including random mutagenesis and screening techniques. Even at this high level of skill, however, the effect of randomly mutating amino acids in the framework regions on antigen binding and functional activity 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 (including location and type) can be made in the framework regions of the claimed antigen-binding fragments that will result in functional variants that still bind to the target antigen (FcyRIIa or PF4) and inhibit platelet activation.
Therefore, the specification is not enabling over the full scope of the claims.
Response to Arguments
Applicant’s arguments filed 03/06/2026 with respect to the rejection of claims under 35 USC 112(a) enablement and 35 USC 112(b) previously set forth in the Final Rejection of 11/07/2025 have been fully considered and are persuasive. In particular, amendments to claims 18, 19, and 21 sufficiently overcome the rejections previously made of record. Therefore, the rejections have been withdrawn. However, upon further consideration, new grounds of rejection are made under 35 USC 112(a) written description and enablement in view of amino acid variation that can be present in the VH and VL chains of the claimed antibodies. Given that claimed antibody CDRs are known in the art, the inventive aspect is undoubtedly in the framework regions of the VH and VL chains. As discussed further in the rejections above, the scope of the claims extends beyond the specific sequences disclosed in the specification by encompassing antibodies having VH and VL framework regions that vary by up to 10% from the recited sequences. The specification does not disclose a representative number of species with the claimed genus nor does it identify common structural features across the full scope of the claimed antibodies sufficient to demonstrate possession. Additionally, there is no guidance provided in the specification about which framework residues can be varied in the claimed antibodies without loss of binding to either FcyRIIa or PF4 and inhibit platelet activation.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 2, 7, 8,12, 15, 16, 17, 18, 19, 20, 21, 23, 24, and 25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7, 14-15, 17, 19, 21, 23-25, 27, 28, 31, 37, and 41 of copending Application No. 18247381. Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims either anticipate or are obvious variants over the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The co-pending claims recite an anti-binding fragment that specifically binds FcγRIIa comprising a VH chain and VL chain joined by a linker (co-pending claims 1 and 2), wherein the antigen-binding fragment is conjugated to an anticoagulant, including each anticoagulant recited in instant claim 8 (co-pending claims 14 and 15). The antigen-binding fragment is a single chain variable fragment (scFv) and the linker is a flexible linker (co-pending claim 19). Further recited is a pharmaceutical composition comprising the antigen-binding fragment (co-pending claim 27); a nucleic acid encoding the antigen binding fragment (co-pending claim 23); a vector comprising the nucleic acid (co-pending claim 24); and a host cell comprising the vector are also recited (co-pending claims 25). Lastly recited is a method of treating a thrombogenic-related disease or a disease related to FcyRIIa-mediated neutrophil activation in a subject, including those diseses recited in instant claims 20 and 21 (co-pending claims 28, 31, and 37). In the method, the antigen binding fragment is administered intravenously from about 5 mg/kg to about 50 mg/kg (co-pending claim 41). Further, it would have been to administer the anti-FcyRIIa to a human subject in order to treat human diseae. The antigen-binding fragment comprises
a VH chain of SEQ ID NO: 15 having 100% sequence identity to SEQ ID NO: 13 of the instant claims and fully comprising the CDRs of SEQ ID NOs: 3-5 of the instant claims; and
a VL chain of SEQ ID NO: 16 having 92.7% sequence identity to SEQ ID NO: 14 of the instant claims and fully comprising the CDRs of SEQ ID NOs: 6-8 of the instant claims (co-pending claim 7).
The minimal structure required for an anti-FcyRIIa antibody to prevent platelet activation includes six CDRs of SEQ ID NOs: 3-8, a VH at least 90% identical to SEQ ID NO: 13, and a VL chain at least 90% identical to SEQ ID NO: 14. Thus, the anti-FcyRIIa antibody of the co-pending claims necessarily prevents platelet activation.
Thus, the co-pending claims meet the limitations of instant claims 1, 2, 7, 8,12, 15, 16, 17, 18, 19, 20, 21, 23, 24, and 25.
Conclusion
No claims are allowable.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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