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 .
Detailed Action
This action is in response to the papers filed November 2, 2025.
Amendments
Applicant's amendments, filed November 2, 2025, is acknowledged. Applicant has cancelled Claims 2-3, 8, 20, and 22-25, and amended Claims 1 and 13-15.
Claims 1, 4-7, 9-19, 21, and 26 are pending and under examination.
Priority
This application is a 371 of PCT/GB2021/051435 filed on June 9, 2021.
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d). A certified copy of foreign patent application UK 2008688.0 filed on June 9, 2020 is provided with the instant application.
Information Disclosure Statement
Applicant has filed an Information Disclosure Statement on November 2, 2025 that has been considered.
The signed and initialed PTO Forms 1449 are mailed with this 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.
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.
1. The prior rejection of Claim 2 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, is/are withdrawn in light of Applicant’s cancellation of the claim.
2. Claim 4 is 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.
Applicant has amended Claim 1 to recite the new limitation “wherein said tumor antigen is release from a tumor cell into the tumor microenvironment”.
Claim 4 fails to further limit Claim 1 because it is axiomatic that in order for the tumor antigen to be released from the tumor cell into the tumor microenvironment, it cannot have a transmembrane domain, lipid anchor, or a signal peptide, as those amino acid motifs retain (syn. not release) the peptide to a lipid membrane, be it intracellular membranes or the cell surface membrane per natural law of cell biology.
The claims fail to recite, and the specification fails to disclose, a first tumor antigen that is released from a tumor cell into the tumor microenvironment, wherein said tumor antigen comprises a transmembrane domain, lipid anchor, or a signal peptide (Claim 1), as opposed to a second tumor antigen that is released from a tumor cell into the tumor microenvironment, wherein said tumor antigen does not comprise a transmembrane domain, lipid anchor, or a signal peptide (Claim 4).
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.
3. Claims 1, 4-7, 9-19, 21, and 26 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.
Applicant has amended Claims 1, 13, and 15 to recite the new limitation “wherein said tumor antigen is release from a tumor cell into the tumor microenvironment”.
The claims suffer from a lack of adequate written description of the nexus, individually and/or in combination and/or subcombinations thereof, between:
i) the CAR antigen binding domain [structure 1] and the corresponding first tumor antigen epitope [structure 2] to which the CAR antigen binding domain binds [function 1];
ii) the first bi-specific protein antigen binding domain [structure 3] and the corresponding second tumor antigen epitope [structure 4], different than the first tumor antigen epitope [structure 2], to which the first bi-specific protein antigen binding domain binds [function 2];
iii) the second bi-specific protein antigen binding domain [structure 5] and the corresponding cell surface antigen [structure 6] to which second first bi-specific protein antigen binding domain binds [function 3]; and
iv) the tumor antigen [structure 7] that is released from a tumor cell into the tumor microenvironment [function 4].
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function ... does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is’).
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
The claims are directed to an enormously vast genus of structurally undisclosed chimeric antigen receptors and bi-specific proteins, each of which are to comprise at least one binding domain [structures] that has the functional properties of binding to an intracellular tumor antigen [structures] having the functional property of being released from a tumor cell into the tumor microenvironment, including tumor antigens whose epitopes comprise a tumor-specific post-translational modification (Claim 9), to wit, phosphorylation (Claim 10).
The claims fail to recite, and the specification fails to disclose, a first tumor antigen of the infinite and/or enormously vast genus of structurally undisclosed tumor antigens that is/are released from a tumor cell into the tumor microenvironment, as opposed to a second tumor antigen of the infinite and/or enormously vast genus of structurally undisclosed tumor antigens that is/are not released from a tumor cell into the tumor microenvironment (Claims 1, 13, and 15).
The claims fail to recite, and the specification fails to disclose, a first tumor antigen that is released from a tumor cell into the tumor microenvironment, wherein said tumor antigen comprises a transmembrane domain, lipid anchor, or a signal peptide (Claim 1), as opposed to a second tumor antigen that is released from a tumor cell into the tumor microenvironment, wherein said tumor antigen does not comprise a transmembrane domain, lipid anchor, or a signal peptide (Claim 4).
The specification discloses fusion proteins such as EML4/ALK (CD246) (e.g. Table 2).
Mano et al (Non-solid oncogenes in solid tumors: EML4–ALK fusion genes in lung cancer, Cancer Sci. 99(12): 2349-2355, 2008) is considered relevant prior art for having taught that ALK fusion proteins such as EML4/ALK, NPM/ALK, and TPM3/ALK each result in intracellular fusion proteins comprising the ALK kinase domain, but not the ALK extracellular domain (e.g. Figure 2).
Walker et al (Tumor Antigen and Receptor Densities Regulate Efficacy of a Chimeric Antigen Receptor Targeting Anaplastic Lymphoma Kinase, Molecular Therapy 25(9): 2189-2201, 2017) is considered relevant prior art for having taught anti-ALK CAR T cell; however, the CAR is directed to full-length ALK (e.g. pg 2189, col. 1, “activating mutations of full-length ALK”), more specifically, the extracellular domain (e.g. pg 2190, col. 1, “ALK48, directed against the extracellular domain of ALK”).
Similarly, Kotani et al (Proximity proteomics identifies cancer cell membrane cis-molecular complex as a potential cancer target, Cancer Science 110: 2607-2619, available online June 22, 2019) is considered relevant prior art for having taught that bi-specific antibodies recognize cell-surface antigens (e.g. Figure 1), shown below:
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whereby said cell surface antigens comprise, e.g. a transmembrane domain and/or lipid anchor, and whereby those of ordinary skill in the art have long-recognized that such proteins comprise a signal peptide in order to be placed into the Golgi before being transported to the cell membrane, as such is natural law of cell biology.
The prior art does not teach, and the specification fails to disclose, chimeric antigen receptors comprising at least one binding domain [structures] that has the functional properties of binding to an intracellular tumor antigen, nor CAR T cells expressing a bi-specific protein comprising at least one binding domain [structures] that has the functional properties of binding to an intracellular tumor antigen in addition to a second binding domain which binds a cell surface antigen.
The Cleveland Clinic (my.clevelandclinic.org/health/body/24949-oncogenes; last visited July 14, 2025) teaches that there are more than 100 different oncogenes to various kinds of cancer.
Fritsch et al (U.S. 2018/0153975) is considered relevant prior art for having disclosed that tumor antigen epitopes may be as many as 10, 15, 20, 25, 30, 35, 40, 45, or 50 amino acids in length (e.g. [0018, 30, 54]).
20^50 = about 1x10^65 structurally undisclosed peptide antigens.
20^40 = 1x10^52 structurally undisclosed peptide antigens.
20^30 = 1x10^39 structurally undisclosed peptide antigens.
20^20 = 1x10^26 structurally undisclosed peptide antigens.
20^10 = 1x10^13 structurally undisclosed peptide antigens.
(www.calculator.net/exponent-calculator.html; last visited July 14, 2025)
The claim lacks adequate written description for the structure/function nexus between the enormously vast genus of structurally undisclosed first and second antigen binding domains that are to have the functional properties of binding the about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed peptides from each of the more than 100 structurally different known oncogenes.
The claims are directed to a first, second, and third antigen binding domains recited at a high level of generality.
The specification discloses, for example, a CD19 antigen binding domain of SEQ ID NO:2 that is 268 amino acids in length (residues 178-445 of SEQ ID NO:2).
20^270 = an infinite genus of structurally undisclosed antigen binding domains.
Thus, the claims reasonably encompass:
a) an infinite genus of structurally undisclosed antigen binding domains that are to have the functional properties of binding the about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed first epitopes of an intracellular tumor antigen from each of the more than 100 structurally different known oncogenes;
in combination with
b) an infinite genus of structurally undisclosed antigen binding domains that are to have the functional properties of binding the about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed second epitopes of an intracellular tumor antigen from each of the more than 100 structurally different known oncogenes;
in combination with
c) an infinite genus of structurally undisclosed antigen binding domains that are to have the functional properties of binding the about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed first epitopes of an enormously vast genus of structurally undisclosed cell surface antigens.
The claims fail to recite, and the specification fails to disclose, a first tumor antigen [structure] of the enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed structurally undisclosed tumor antigen peptides that is/are released from a tumor cell into the tumor microenvironment [function], as opposed to a second tumor antigen [structure] of the enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed structurally undisclosed tumor antigen peptides that is/are not released from a tumor cell into the tumor microenvironment [function] (Claims 1, 13, and 15).
It is axiomatic that in order for the tumor antigen to be released from the tumor cell into the tumor microenvironment, it cannot have a transmembrane domain, lipid anchor, or a signal peptide, as those amino acid motifs retain (syn. not release) the peptide to a lipid membrane, be it intracellular membranes or the cell surface membrane per natural law of cell biology.
The claims fail to recite, and the specification fails to disclose, a first tumor antigen [structure] of the enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed structurally undisclosed tumor antigen peptides that is released from a tumor cell into the tumor microenvironment [function], wherein said tumor antigen comprises a transmembrane domain, lipid anchor, or a signal peptide (Claim 1), as opposed to a second tumor antigen [structure] of the enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed structurally undisclosed tumor antigen peptides that is released from a tumor cell into the tumor microenvironment [function], wherein said tumor antigen does not comprise a transmembrane domain, lipid anchor, or a signal peptide (Claim 4).
The claims fail to recite, and the specification fails to disclose, a first CAR binding domain [structure] of the infinite genus of structurally undisclosed antigen binding domains that binds to [function] the enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed first tumor antigen epitopes [structure], as opposed to a second CAR binding domain [structure] of the infinite genus of structurally undisclosed antigen binding domains that does not bind [function] the enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed first tumor antigen epitopes [structure] (Claims 1, 13, and 15).
The claims fail to recite, and the specification fails to disclose, a first CAR binding domain [structure] of the infinite genus of structurally undisclosed antigen binding domains that binds to [function] the enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed first tumor antigen epitopes [structure] that is/are released from a tumor cell into the tumor microenvironment [function], as opposed to a second CAR binding domain [structure] of the infinite genus of structurally undisclosed antigen binding domains that binds [function] the enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed first tumor antigen epitopes [structure] that is/are not released from a tumor cell into the tumor microenvironment [function] (Claims 1, 13, and 15).
The claims fail to recite, and the specification fails to disclose, a first bi-specific protein binding domain [structure] of the infinite genus of structurally undisclosed antigen binding domains that binds to [function] the enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed second tumor antigen epitopes [structure] that is/are different from the enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed first tumor antigen epitopes [structure], as opposed to a second bi-specific protein binding domain [structure] of the infinite genus of structurally undisclosed antigen binding domains that is not able to bind [function] the enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed second tumor antigen epitopes [structure] that is/are different from the enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed first tumor antigen epitopes [structure] (Claims 1, 13, and 15).
The claims fail to recite, and the specification fails to disclose, a first bi-specific protein binding domain [structure] of the infinite genus of structurally undisclosed antigen binding domains that binds to [function] the enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed second tumor antigen epitopes [structure] that is/are different from the enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed first tumor antigen epitopes [structure] that is/are released from a tumor cell into the tumor microenvironment [function], as opposed to a second bi-specific protein binding domain [structure] of the infinite genus of structurally undisclosed antigen binding domains that binds [function] the enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed second tumor antigen epitopes [structure] that is/are different from the enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed first tumor antigen epitopes [structure] that is/are not released from a tumor cell into the tumor microenvironment [function] (Claims 1, 13, and 15).
Given the highly diverse structural nature of antibodies, particularly in the CDRs, one of ordinary skill in the art generally cannot envision the structure of an antibody by knowing its binding characteristics.
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 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 a given antibody. 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 the required conformation of the CDRs are required in order to produce a protein having antigen-binding function; and further, that proper association of heavy and light chain variable regions is required in order to form functional binding sites.
MacCallum et al (Antibody-antigen Interactions: Contact Analysis and Binding Site Topography, J. Mol. Biol. 262:732-745, 1996) 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 (pg 733, col. 2) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (pg 735, col. 1).
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 (A peptide mimetic of an anti-CD4 monoclonal antibody by rational design, Biochem. Biophys. Res. Comm. 307:198-205, 2003), who 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 (pg 199, col. 1). Thus, while one can make the statement that CDRs from a single antibody chain make a significant contribution in the antigen binding, the CDR domains from a single chain are not the only residues that influence binding, and in fact the prior art does not support that CDR domains from a single chain alone are sufficient to define the binding specificity of an antibody.
Goel et al (Plasticity within the Antigen-Combining Site May Manifest as Molecular Mimicry in the Humoral Immune Response, J. Immunol. 173: 7358-7367, 2004) taught the generation of monoclonal antibodies directed to the same antigen, whereby three antibodies that bind to the same 12-mer epitope/antigen have substantial amino acid diversity in the CDRs (Figure 3) and binding kinetics (Table III, Figure 6).
Poosarla et al (Computational De Novo Design of Antibodies Binding to a Peptide With High Affinity, Biotech. & Bioengin. 114(6): 1331-1342, 2017) designed scFv fragments that bind to the same 12-mer epitope/antigen, and demonstrate substantial diversity in said antibody amino acid sequences (Figure 3). It appears that even though all antibodies bind to the same 12-mer they bind to different epitopes within it.
Edwards et al (The Remarkable Flexibility of the Human Antibody Repertoire; Isolation of Over One Thousand Different Antibodies to a Single Protein, BLyS, J. Mol. Biol. 334: 103-118, 2003) taught the ability to identify over 1000 antibodies composed of structurally different amino acid sequences that bind to a single antigen (see entire paper).
Thus, knowing the identity of the target antigen does not inform the artisan as to the amino acid sequence of the corresponding peptide or antibody that can bind to said target antigen.
In contrast to the prior art’s use of a defined antigen or epitope upon which to identify antibodies that bind to said defined antigen or epitope, the specification fails to disclose:
a first chimeric antigen receptor whose antigen binding domain necessarily and predictably binds a tumor antigen of an intracellular oncogene, nor
a first tumor antigen binding domain of a bi-specific protein that binds a tumor antigen of an intracellular oncogene in combination with a second binding domain that binds a cell surface antigen.
Moreira et al (Hot spots—A review of the protein–protein interface determinant amino-acid residues, Proteins 68: 803-812, 2007) is considered relevant prior art for having taught Protein–protein interactions are very complex and can be characterized by their size,
shape, and surface complementarity (e.g. pg 803, Protein-Protein). The hydrophobic and electrostatic interactions they establish, as well as the flexibility of the molecules involved, are very significant.
Moreira et al taught that in a protein–protein interface, a small subset of the buried amino acids typically contribute to the majority of binding affinity as determined by the change in the free energy of binding. Although there is no purely geometric reason, these energetic determinants are compact, centralized regions of residues crucial for protein association (e.g. pg 804, col. 2).
Moreira et al taught that most interfaces are optimal tight-fitting regions characterized by complementary pockets scattered through the central region of the interface, and enriched in structurally conserved residues. These pockets are classified as ‘‘complementary’’ because there is a large complementarity both in shape and in the juxtaposition of hydrophobic and hydrophilic hot spots, with buried charged residues forming salt bridges and hydrophobic residues from one surface fitting into small nooks on the opposite face. Usually, the hot spot of one face packs against the hot spot of the other face establishing a region determinant for complex binding (e.g. pg 806, col. 1). Complementarity is basically affected by the size of the buried surface, alignment of polar and nonpolar residues, number of buried waters, and the packing densities of atoms involved in the protein–protein interface. Packing defects at the protein–protein interface result in these gaps or pockets, and it is unclear whether unfilled pockets contain water molecules or how the dynamics of water molecules entering and escaping these pockets may affect binding stability (e.g. pg 807, col. 2). Moreira et al taught that common methodology to determine hot spot locations on the artisan’s protein of interest, alanine-scanning mutagenesis is slow and labor-intensive (e.g. pg 804, col. 1). Similarly, systematic mutagenesis is very laborious and time-consuming to perform, as individual mutant proteins must be purified and analyzed separately (e.g. pg 808, col. 2).
Ng et al (Predicting the Effects of Amino Acid Substitutions on Protein Function, Annual Review Genomics Human Genetics 7: 61-80, 2006) is considered relevant prior art for having taught that non-synonymous nucleotide changes which introduce amino acid changes in the corresponding protein have the largest impact on human health. Most algorithms to predict amino acid substation consequences of protein function indicate about 25% to 30% of amino acid changes negatively affect protein function (Abstract). Existing prediction tools primarily focus on studying the deleterious effects of single amino acid substitutions through examining amino acid conservation at the position of interest among related sequences, an approach that is not directly applicable to multiple amino acid changes, including insertions or deletions. Ng et al taught that 83% of disease-causing mutations affect protein stability (e.g. pg 63, col. 1), which in this case, would affect the ability of:
a) the infinite genus of structurally undisclosed antigen binding domains to bind the about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed first epitopes of an intracellular tumor antigen from each of the more than 100 structurally different known oncogenes, respectively;
in combination with
b) the infinite genus of structurally undisclosed antigen binding domains to bind the about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed second epitopes of an intracellular tumor antigen from each of the more than 100 structurally different known oncogenes, respectively;
in combination with
c) the infinite genus of structurally undisclosed antigen binding domains to bind the about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed first epitopes of an enormously vast genus of structurally undisclosed cell surface antigens, respectively.
Prediction of protein structure by homology and/or algorithm is notoriously difficult, as one of ordinary skill in the art would immediately understand.
Consequently, the gap between the number of as-yet to be discovered protein sequences of the claimed, but not structurally disclosed, infinite genus of structurally and functionally undisclosed first, second, and third antigen binding domains that are to necessarily and predictably have the functional properties of binding to their enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed target antigens, respectively, is considered to be tremendous, notoriously difficult, slow, very laborious and time-consuming for the ordinary artisans to determine for themselves that which Applicant has failed to disclose.
Therefore, based on the discussions above concerning the specific examples of structurally similar proteins that have different functions, along with the art's recognition that one cannot rely upon structural similarity alone to determine functionality, the specification fails to reasonably inform the ordinary artisan how to make and use the claimed infinite genus of structurally and functionally undisclosed first, second, and third antigen binding domains that are to necessarily and predictably have the functional properties of binding to their enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed target antigens, respectively.
Disclosure of putative structures having a theorized function in the absence of experimental data demonstrating the theorized function is insufficient to demonstrate possession of a representative number of species 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 claimed invention.
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. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”).
Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)
The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 “merely by clearly describing one embodiment of the thing claimed.” LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005).
For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are “representative of the full variety or scope of the genus,” or by the establishment of “a reasonable structure-function correlation.” Such correlations may be established “by the inventor as described in the specification,” or they may be “known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014)
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, knowing that the initial tumor antigen is an intracellular protein does not tell you anything at all about the structure (amino acid sequence(s)) of the enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed first epitopes and second epitopes, respectively, nor the structure (amino acid sequence(s)) of the infinite genus of structurally undisclosed antigen binding domains that are to necessarily and predictably have the functional properties of binding to said enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed first epitopes and second epitopes, respectively.
Similarly, knowing that the initial cell surface antigen is expressed on the surface of a cell does not tell you anything at all about the structure (amino acid sequence(s)) of the enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed cell surface antigen epitopes, nor the structure (amino acid sequence(s)) of the infinite genus of structurally undisclosed antigen binding domains that are to necessarily and predictably have the functional properties of binding to said enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed cell surface antigen epitopes, respectively.
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that Applicant seeks to claim for themselves:
a) an infinite genus of structurally undisclosed antigen binding domains that are to have the functional properties of binding the about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed first epitopes of an intracellular tumor antigen from each of the more than 100 structurally different known oncogenes, respectively;
in combination with
b) an infinite genus of structurally undisclosed antigen binding domains that are to have the functional properties of binding the about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed second epitopes of an intracellular tumor antigen from each of the more than 100 structurally different known oncogenes, respectively;
in combination with
c) an infinite genus of structurally undisclosed antigen binding domains that are to have the functional properties of binding the about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed first epitopes of an enormously vast genus of structurally undisclosed cell surface antigens, respectively.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent are included in the basis of the rejection because they encompass the embodiments of Claims 1, 13, 15-16, 18-19, and 21, but they do not correct the primary deficiencies of the independent claims.
Response to Arguments
Applicant argues that the specification discloses the use of numerous different antibodies, including anti-phosphorylation-specific antibodies and tumor antigens (Tables 2-4).
Applicant’s argument(s) has been fully considered, but is not persuasive.
As a first matter, the court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
Instant claims encompass an infinite genus of structurally undisclosed antigen binding domains that are to have the functional properties of binding the about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed first epitopes of an intracellular tumor antigen from each of the more than 100 structurally different known oncogenes, respectively;
in combination with
b) an infinite genus of structurally undisclosed antigen binding domains that are to have the functional properties of binding the about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed second epitopes of an intracellular tumor antigen from each of the more than 100 structurally different known oncogenes, respectively;
in combination with
c) an infinite genus of structurally undisclosed antigen binding domains that are to have the functional properties of binding the about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed first epitopes of an enormously vast genus of structurally undisclosed cell surface antigens, respectively.
Those of ordinary skill in the art would immediately recognize that the few species disclosed in Tables 2-4 simply do not adequately represent the infinite genus of molecules encompassed by the independent claims.
Those of ordinary skill in the art would immediately recognize that the few species disclosed in Tables 1-8 simply do not adequately describe the infinite and/or enormously vast genus of structurally undisclosed first tumor antigens that is/are released from a tumor cell into the tumor microenvironment, as opposed to an infinite and/or enormously vast genus of structurally undisclosed second tumor antigens that is/are not released from a tumor cell into the tumor microenvironment (Claims 1, 13, and 15).
As a second matter, Tables 1-8 do not disclose these antigens to have the recited functional properties recited in independent Claims 1, 13, and 15, to wit, “released from a tumor cell into the tumor microenvironment”, let alone the respective sub-genera of Claims 4-5 and/or 9-10 recited at a high level of generality.
Applicant argues that Example 1 discloses a proof-of-principle, whereby the HL60 cells release intracellular eGFP antigens into their microenvironment.
Applicant’s argument(s) has been fully considered, but is not persuasive. Example 1 makes use of a specific CAR comprising a specific amino acid sequence that binds to eGFP. However, Example 1 fails to disclose the amino acid sequence of said eGFP CAR, nor the antigen/epitope of eGFP to which said eGFP CAR binds.
Those of ordinary skill in the art would immediately recognize that the single eGFP CAR species disclosed in Example 1 simply does not adequately describe the infinite and/or enormously vast genus of structurally undisclosed first CAR binding domain, second binding domain of the bi-specific protein, and/or tumor antigens that is/are released from a tumor cell into the tumor microenvironment, as opposed to an infinite and/or enormously vast genus of structurally undisclosed second tumor antigens that is/are not released from a tumor cell into the tumor microenvironment (Claims 1, 13, and 15).
Applicant argues that Example 5 discloses a p53 tumor antigen comprising a R273H mutation, and a CAR that recognizes said tumor antigen.
Applicant’s argument(s) has been fully considered, but is not persuasive. Example 5 makes use of a specific CAR comprising a specific amino acid sequence that binds to p53 R273H mutation. However, Example 5 fails to disclose the amino acid sequence of said p53 R273H CAR, nor the amino acid sequence of the second binding domain of the bi-specific protein that is to also bind p53 R273H.
Those of ordinary skill in the art would immediately recognize that the single p53 R273H CAR species disclosed in Example 5 simply does not adequately describe the infinite and/or enormously vast genus of structurally undisclosed first CAR binding domain, second binding domain of the bi-specific protein, and/or tumor antigens that is/are released from a tumor cell into the tumor microenvironment, as opposed to an infinite and/or enormously vast genus of structurally undisclosed second tumor antigens that is/are not released from a tumor cell into the tumor microenvironment (Claims 1, 13, and 15).
The claims suffer from a lack of adequate written description of the nexus, individually and/or in combination and/or subcombinations thereof, between:
i) the CAR antigen binding domain [structure 1] and the corresponding first tumor antigen epitope [structure 2] to which the CAR antigen binding domain binds [function 1];
ii) the first bi-specific protein antigen binding domain [structure 3] and the corresponding second tumor antigen epitope [structure 4], different than the first tumor antigen epitope [structure 2], to which the first bi-specific protein antigen binding domain binds [function 2];
iii) the second bi-specific protein antigen binding domain [structure 5] and the corresponding cell surface antigen [structure 6] to which second first bi-specific protein antigen binding domain binds [function 3]; and
iv) the tumor antigen [structure 7] that is released from a tumor cell into the tumor microenvironment [function 4].
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function ... does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is’).
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that Applicant seeks to claim for themselves:
a) an infinite genus of structurally undisclosed antigen binding domains that are to have the functional properties of binding the about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed first epitopes of an intracellular tumor antigen from each of the more than 100 structurally different known oncogenes, respectively;
in combination with
b) an infinite genus of structurally undisclosed antigen binding domains that are to have the functional properties of binding the about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed second epitopes of an intracellular tumor antigen from each of the more than 100 structurally different known oncogenes, respectively;
in combination with
c) an infinite genus of structurally undisclosed antigen binding domains that are to have the functional properties of binding the about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed first epitopes of an enormously vast genus of structurally undisclosed cell surface antigens, respectively.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
Thus, for the reasons outlined above, it is concluded that the claims do no