DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendment, filed 06/26/2023, has been entered.
Applicant’s substitute specification, filed 11/07/2025, has been entered.
Claims 1-3, 6-8 and 11-14 are pending and currently under examination as they read on a SARS-CoV-2 RBD-specific monoclonal antibody.
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.
Claims 7 and 8 are 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 7-8 recite the SARS-CoV-2 RBD-specific monoclonal antibody comprises a linear epitope. The instant specification discloses that the antibody binds to the linear epitope (Figure 3). The claim limitation mentioned above renders the claims indefinite because it is not clear whether the antibody has a linear epitope attached to it or the antibody binds to a linear epitope. Therefore, the claims are indefinite.
Claim 8 recites the limitation "the linear epitope". However, there is insufficient antecedent basis for this limitation in the base claim 6 which claim 8 depends from. Therefore, the claim is indefinite.
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.
Claims 1-3, 6-8 and 11-14 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.
The present claims read on an antibody have “a heavy chain having an amino acid sequence set forth in SEQ ID NO: 1 and a light chain having an amino acid sequence set forth in SEQ ID NO: 2.” Because the claim refers to “an amino acid sequence” set forth in the indicated sequence, this is an indication that the antibody need not have the complete sequence found therein, i.e., the claim reads on antibodies that can comprise some of the CDRs in the indicated sequences, none of them, or fragments of the CDRs. Since a complete collection of 6 CDRs is required, and as the application does not provide teachings of variants of the antibody with modifications to the CDRs, or with different sets of CDRs, there does not appear to be adequate written description support for the claimed genus of CDRs which reads on any antibody that shares a partial sequence with any portion of each of SEQ ID Nos: 1 and 2 for the following reasons:
The written description requirement for a claimed genus may be satisfied through description of 1) a representative number of species OR 2) disclosure of relevant identifying characteristics, i.e., functional characteristics coupled with a known or disclosed correlation between function and structure.
Representative Species
With regard to representative number of species, the instant specification disclosed a single species of the SARS-CoV-2 RBD-specific monoclonal antibody, i.e., comprising heavy and light chain of the sequences set forth in SEQ ID NOs: 1 and 2. However, the single disclosed species is not sufficient to represent the entire genus.
A “representative number of species" means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The “structural features common to the members of the genus” needed for one of skill in the art to 'visualize or recognize' the members of the genus takes into account the state of the art at the time of the invention. For example, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural “stepping stone” to the corresponding chimeric antibody, but not to human antibodies. Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875 (Fed. Cir. 2011).
The size of the claimed antibody genus comprises substantial variations as one of skill in the art is well aware of the high level of polymorphism and complex nature of immunoglobulins. Schroeder et al. taught that through somatic variation, combinatorial rearrangement of individual gene segments and combinatorial association between different L and H chains, the repertoire of antibody diversity can have greater than 1016 different immunoglobulins (J Allergy Clin Immunol 2010, 125:S41-S52).
Moreover, it is well-known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope. For example, Lloyd et al. taught that over hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Protein Engineering, Design & Selection 2009, 22:159-168; see, e.g., Discussion).
Therefore, one species is not representative of the claimed genus encompassing the substantial variation due to the high level of polymorphism of antibodies as exemplified by the above references.
Structure-function correlation
While the term “antibody” does impart some structure, the structure that is common to antibodies is generally unrelated to antigen-binding function because antibody CDRs are necessary for binding and they are highly diverse in structure and their sequence does not correlate to binding in a predictable fashion.
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs (or hypervariable regions), 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. 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 as evidenced by Rudikoff et al. (Proc Natl Acad Sci USA 1982 Vol 79 page 1979). Rudikoff et al. teach 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. MacCallum et al. (J. Mol. Biol. 1996 262, 732-745), analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (see page 733, right col) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left col.). Pascalis et al. (The Journal of Immunology (2002) 169, 3076-3084) 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. (BBRC 2003, 307:198-205), 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 (see entire document). 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. (J. Mol. Biol. (2002) 320, 415-428), additionally state that antigen binding is primarily mediated by the CDRs more highly conserved framework segments which connect the CDRs are mainly involved in supporting the CDR loop conformations and in some cases framework residues also contact antigen (page 416, left col.). Chen et al. (J. Mol. Bio. (1999) 293, 865-881) describe high affinity variant antibodies binding to VEGF wherein the results show that the antigen binding site is almost entirely composed of residues from heavy chain CDRs, CDR-H1, H2, H3 (page 866). Wu et al. (J. Mol. Biol. (1999) 294, 151-162) state that it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity due in part to the large conformational change in antibodies that accompany antigen binding (page 152 left col.) but certain residues have been identified as important for maintaining conformation. Padlan et al. (PNAS 1989, 86:5938-5942) described the crystal structure of an antibody-lysozyme complex where all 6 CDRs contribute at least one residue to binding and one residue in the framework is also in contact with antigen. In addition, Lamminmaki et al. (JBC 2001, 276:36687-36694) describe the crystal structure of an anti-estradiol antibody in complex with estradiol where, although CDR3 of VH plays a prominent roll, all CDRs in the light chain make direct contact with antigen (even CDR2 of VL, which is rarely directly involved in hapten binding). Recently, studies have shown that changing in CDRs even alter Fc binding to the Fc receptor and pharmacokinetics (Piche-Nicholas et al. MABS 2018, 10:81-94).
Given the highly diverse nature of antibodies, particularly in the CDRs, by claiming a genus of SARS-CoV-2 RBD-specific monoclonal antibodies defined by any sequences within SEQ ID NO: 1 and 2 as the heavy and light chain, one of skill in the art cannot envision the structure of an antibody by knowing its binding characteristics. Therefore, the claims do not satisfy the written description requirement as the structure-function correlation of the claimed genus not sufficiently described.
Given the well-known high level of polymorphism of immunoglobulins / antibodies, the skilled artisan would not have been in possession of the vast repertoire of antibodies and the unlimited number of antibodies encompassed by the claimed invention; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genera of DPP3 binders broadly encompassed by the claimed invention. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genera.
Applicant is invited to amend claim 1 to recite “the amino acid sequence set forth” in order to obviate this rejection.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-3, 6-8, 11-14 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (a product of nature) without significantly more.
The present claims are directed to a SARS-CoV-2 RBD-specific monoclonal antibody.
The claims are directed to a statutory category, e.g., a composition of matter (Step 1: YES). The claims are then analyzed in Step 2A (Prong one) to determine whether it is directed to any judicial exception. The present claims recite a SARS-CoV-2 RBD-specific monoclonal antibody. Claim 2 recites that the antibody is obtained by sorting RBD-specific memory B cells and then acquiring antibody variable region cDNA from mRNA of the memory B cells. The instant specification discloses that the memory B cell is from blood of a patient recovered from COVID-19 (page 6, paragraph 0033). Using PCR to sequence and recombinantly express the antibody does not alter its structure, function, or biological activity in a manner that renders it markedly different from the naturally occurring antibody. Accordingly, the claims recite a product of nature, which is a recognized judicial exception under §101(Step 2A, prong one: YES).
The claims are then analyzed in Step 2A (Prong two). The claims merely recite the antibody itself, described by its natural origin (i.e., isolated from memory B cells), without any additional elements that integrate the antibody into a practical application. The intended use (i.e., for preparing a reagent or a medicament for detecting or diagnosing SARS-CoV-2) recited in the claims does not add patentable weight. Furthermore, the claimed antibody intended for said preparation, as formulated in the present claims, retains its naturally occurring structure and properties. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. Thus, the claimed components as a whole do not display markedly different characteristics compared to the closest naturally occurring counterpart. Accordingly, the Step 2A (Prong two) is NO.
Furthermore, the claims do not include additional elements that amount to significantly more than the natural antibody itself. The act of “obtaining by sorting RBD-specific memory B cells and then acquiring antibody variable region cDNA from mRNA of the RBD-specific memory B cells” is a well-understood, routine, and conventional laboratory technique and does not confer eligibility. Furthermore, the process of obtaining the antibody does not render the antibody structurally different from its naturally occurring counterpart. The claim does not recite any inventive concept that transforms the nature of the claim into patent-eligible subject matter. Because the claims are directed to a naturally occurring antibody and lacks additional elements that amount to significantly more than the judicial exception, the present claims are not patent eligible under 35 U.S.C. §101.
Conclusion
No claim is allowed.
SEQ ID NOs: 1 and 2 are free of prior art.
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/SHARON X WEN/Primary Examiner, Art Unit 1641