DETAILED ACTION
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 .
Claim Status
The claim set filed on 3 June 2024 contains claims 1-20, which are currently pending.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-10) in the reply filed on 6 July 2026 is acknowledged. Claims 11-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 6 July 2026. Claims 1-10 will be examined on the merits herein.
After further search and consideration, the requirement for the election of species of sequences in claims 1-5 is hereby withdrawn.
Priority
The instant application claims priority to U.S. Provisional Application 63/470,375 (filed 1 June 2023). Therefore, the effective filing date of claims 1-10 is 1 June 2023.
Information Disclosure Statement
The information disclosure statement filed 12 August 2024 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because no copy of Non-Patent Literature reference no. 1 (Kindt et al.) has been provided. It has been placed in the application file, but the information referred to therein has not been considered as to the merits. Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim Rejections - 35 USC § 112
Claim 7 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 7 contains the trademark/trade name NANOBODY®. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe an antibody structure and, accordingly, the identification/description is indefinite. Clarification is requested.
Claim Rejections - 35 USC § 112(a)
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.
Claims 1-10 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. This is a written description rejection.
The claims are broadly drawn to an isolated antibody, epitope binding fragment, or variant thereof that binds to Rox-P. Claim 1 recites that the antibody, epitope binding fragment, or variant thereof is “(a) an immunoglobulin heavy chain variable region (VH) at least 90% identical to the amino acid sequence set forth in one of SEQ ID NOS: 1-4; or (b) an immunoglobulin light chain variable region (VL) at least 90% identical to the amino acid sequence set forth in one of SEQ ID NOS: 5-8; or (c) both (a) and (b) above.” The broadest reasonable interpretation of the claim is that either the heavy chain or light chain alone is sufficient to bind Rox-P and that any combination of the recited heavy and light chain sequences (i.e., greater than four antibody structures) are capable of binding Rox-P. Claims 3 and 4 recite limitations identical to limitations in claim 1 (a) and (b), respectively, and therefore have the same interpretation.
Claim 2 recites, “(a) a HC-CDR1 comprising an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 9,15, 21, or 27; (b) a HC-CDR2 comprising an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 10,16, 22, or 28; (c) a HC-CDR3 comprising an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 11,17, 23, or 29; (d) a LC-CDR1 comprising an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 12,18, 24, or 30; (e) a LC-CDR2 comprising an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 13, 19, 25, or 31; or (f) a LC-CDR3 comprising an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 14, 20, 26, or 32.” The broadest reasonable interpretation of this claim is that the antibody, epitope binding fragment, or variant of claim 1 may comprise any combination of CDRs (e.g., comprising SEQ ID NO: 9 as HC-CDR1, SEQ ID NO: 16 as HC-CDR2, SEQ ID NO: 23 as HC-CDR3, etc.).
Claim 5 recites, “wherein the antibody comprises:
a heavy chain variable region having the sequence of SEQ ID NO. 1 and a light chain variable region having the sequence of SEQ ID NO. 5;
a heavy chain variable region having the sequence of SEQ ID NO. 1 and a light chain variable region having the sequence of SEQ ID NO. 6;
a heavy chain variable region having the sequence of SEQ ID NO. 1 and a light chain variable region having the sequence of SEQ ID NO. 7;
a heavy chain variable region having the sequence of SEQ ID NO. 1 and a light chain variable region having the sequence of SEQ ID NO. 8;
a heavy chain variable region having the sequence of SEQ ID NO. 2 and a light chain variable region having the sequence of SEQ ID NO. 5;
a heavy chain variable region having the sequence of SEQ ID NO. 2 and a light chain variable region having the sequence of SEQ ID NO. 6;
a heavy chain variable region having the sequence of SEQ ID NO. 2 and a light chain variable region having the sequence of SEQ ID NO. 7;
a heavy chain variable region having the sequence of SEQ ID NO. 2 and a light chain variable region having the sequence of SEQ ID NO. 8;
a heavy chain variable region having the sequence of SEQ ID NO. 3 and a light chain variable region having the sequence of SEQ ID NO. 5;
a heavy chain variable region having the sequence of SEQ ID NO. 3 and a light chain variable region having the sequence of SEQ ID NO. 6;
a heavy chain variable region having the sequence of SEQ ID NO. 3 and a light chain variable region having the sequence of SEQ ID NO. 7;
a heavy chain variable region having the sequence of SEQ ID NO. 3 and a light chain variable region having the sequence of SEQ ID NO. 8;
a heavy chain variable region having the sequence of SEQ ID NO. 4 and a light chain variable region having the sequence of SEQ ID NO. 5;
a heavy chain variable region having the sequence of SEQ ID NO. 4 and a light chain variable region having the sequence of SEQ ID NO. 6;
a heavy chain variable region having the sequence of SEQ ID NO. 5 and a light chain variable region having the sequence of SEQ ID NO. 7;
or a heavy chain variable region having the sequence of SEQ ID NO. 6 and a light chain variable region having the sequence of SEQ ID NO. 8.”
The claims seek to limit the structure of the antibody by describing the antigen to which the antibody binds, Rox-P. However, disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional. See Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017)("knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies"); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1351-52, 97 USPQ2d 1870, 1877 (Fed. Cir. 2011) (patent disclosed the antigen the claimed antibody was supposed to bind, but did not disclose any antibodies with the specific claimed properties). See also MPEP 2163.II.A.3(a).
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin.
It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. MacCallum et al. (1996; PTO-892) analyzed many different antibodies for interactions with antigen and state that while no single residue is in contact with the antigen in all structures and CDR3 of the heavy and light chain dominate (pg. 733, paragraph bridging columns), contacts are more common at CDR residues which are located centrally within the combining site and non-contacting residues within the CDRs are important in defining "canonical" conformations (Abstract.). Pascalis et al. (2002; PTO-892) demonstrate that grafting of the CDRs into a human framework was performed by grafting CDR residues and maintaining framework residues that were deemed essential for preserving the structural integrity of the antigen binding site (see page 3079, right col.). Although abbreviated CDR residues were used in the constructs, some residues in all 6 CDRs were used for the constructs (see page 3080, left col.). The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is underscored by Casset et al. (2003; PTO-892) which constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs (Abstract). Casset et al. also states that although CDR H3 is at the center of most if not all antigen interactions, clearly other CDRs play an important role in the recognition process (page 199, left col.) and this is demonstrated in this work by using all CDRs except L2 and additionally using a framework residue located just before the H3 (see page 202, left col.). Vajdos et al. (2002; PTO-892) additionally state that antigen binding is primarily mediated by the CDRs and that the more highly conserved framework segments which connect the CDRs are mainly involved in supporting the CDR loop conformations although in some cases framework residues also contact the antigen (page 416, left col.).
Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function. Rudikoff et al. (1982; PTO-892) teaches that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function (Abstract). Thus, the art demonstrates that the antibody structure correlated with its antigen-binding function is six CDRs, the sequence of each CDR, and the position of each CDR. In or der to demonstrate possession of the antibody, epitope binding fragment, or variant capable of binding Rox-P, one must describe a sufficient variety of species of antibody.
MPEP 2163(II)(A)(3)(a)(ii) states (emphasis added):
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), 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 inventor was in possession of the claimed genus (see i)(C) above)….
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
In contrast to the broad genus of antibodies claimed, the applicant reduces to practice four antibodies capable of binding Rox-P: 2H2F3, 3E10E3, 4D8H1, and 5F3D11 (Table1). Each of these antibodies has a specific combination of heavy and light chain sequences: 2H2F3 has a heavy chain of SEQ ID NO: 3 (i.e., not less than 100% identity) and a light chain of SEQ ID NO: 7, 3E10E3 has a heavy chain of SEQ ID NO: 2 and a light chain of SEQ ID NO: 6, 4D8H1 has a heavy chain of SEQ ID NO: 4 and a light chain of SEQ ID NO: 8, and 5F3D11 has a heavy chain of SEQ ID NO: 1 and a light chain of SEQ ID NO: 5 (Table 1). Thus, the specification teaches that SEQ ID NOs: 1-4 are heavy chains and SEQ ID NOs: 5-8 are light chains, in contrast to the combination of heavy and light chain sequences disclosed in claims 1 and 3-5. The specification also has not taught a heavy chain with less than 100% identity to one of SEQ ID NOs: 1-4 or a light chain with less than 100% identity to one of SEQ ID NOs: 5-8 as capable of binding Rox-P. Each of these antibodies also has a specific combination of CDRs: 2H2F3 comprises SEQ ID NOs: 21-26 corresponding to HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3, respectively; 3E10E3 comprises SEQ ID NOs: 15-20 corresponding to HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3, respectively; 4D8H1 comprises SEQ ID NOs: 27-32 corresponding to HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3, respectively; and 5F3D11 comprises SEQ ID NOs: 9-14 corresponding to HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3, respectively (Table 1). Thus, the specification describes only four combinations of CDRs that are 100% identical to the recited sequences that are capable of binding Rox-P, in contrast to the various combinations disclosed in claim 2.
While the specification does describe antibodies comprising the full scope of heavy and light chain combinations disclosed in claims 1 and 3-5 and the combinations of CDRs disclosed in claim 2, the specification does not provide any evidence that the full scope of heavy and light chain combinations or CDR combinations result in an antibody structure that is capable of binding Rox-P. The art at the time of filing does not remedy this deficiency because prior work has demonstrated that the arrangement and position of each of the six CDRs is critical to the antigen-binding function; thus, one of ordinary skill in the art would not predict that combining different heavy and light chains (or CDRs) from antibodies capable of binding an antigen would result in another antibody capable of binding that same antigen.
The applicant has claimed a broad genus of antibodies, but the applicant has only reduced to practice two polyclonal antibody mixtures that bind the claimed polypeptide. Therefore, claims 1-10 are rejected for failing to provide written description of the antibody structures because they fail to demonstrate possession of a representative number of species within the claimed genus.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 3-4 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 3, which depends upon claim 1, recites, “wherein the VH comprises an amino acid sequence at least 90% identical to the amino acid sequence set forth in any one of SEQ ID NOs: 1-4.” This fails to further limit the scope of claim 1 because this limitation has the same scope as that of (a) of claim 1.
Claim 4, which depends upon claim 1, recites, “wherein the VL comprises an amino acid sequence at least 90% identical to the amino acid sequence set forth in any one of SEQ ID NOs: 5-8.” This fails to further limit the scope of claim 1 because this limitation has the same scope as that of (b) of claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BAILEY M MORGAN whose telephone number is (703)756-5388. The examiner can normally be reached M-F 9-5 ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, SAMIRA JEAN-LOUIS can be reached at (571) 270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BAILEY M MORGAN/Examiner, Art Unit 1645
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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