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 21, 2025.
Amendments
Applicant's response and amendments, filed November 21, 2025, is acknowledged. Applicant has cancelled Claims 2-7, 10-12, 15-16, 19-20, 22, 25, 27-30, 33, 35, 37-40, 42-43, 45-46, 48-50, 52, 54-58, and 60, and withdrawn Claims 1, 8, 14, 17-18, 21, 23-24, 26, 31-32, 34, 36, 41, 44, 47, 51, 53, 59, and 61-68.
Claims 1, 8-9, 13-14, 17-18, 21, 23-24, 26, 31-32, 34, 36, 41, 44, 47, 51, 53, 59, and 61-68 are pending.
Election/Restrictions
Applicant has elected without traverse the invention of Group IV, claim(s) 9 and 13, drawn to a TCR polypeptide comprising the amino acid SEQ ID NO recited in the Markush Group, and a nucleic acid encoding said TCR polypeptide.
Within Group IV, Applicant has elected without traverse the following species, wherein:
i) the alternative peptide SEQ ID NO is SEQ ID NO:44, as recited in Claim 1;
ii) the alternative TCR polypeptide SEQ ID NO is TCRalpha chain SEQ ID NO:29 and TCRbeta chain SEQ ID NO:30, as recited in Claim 9;
iii) the alternative method step is in vitro, as recited in Claim 21;
iv) the alternative means of genetic modification is lipid-based particles, as recited in Claim 53;
v) the alternative structural modification is particles functionalized with a targeting molecule on their surface, as recited in Claim 53(i);
vi) the alternative additional method step is administering a polynucleotide encoding the antigen, as recited in Claim 44; and
vii) the alternative method step is administering the immune effector cells genetically modified to express the TCR, as recited in Claim 34(i).
Claims 1, 8-9, 13-14, 17-18, 21, 23-24, 26, 31-32, 34, 36, 41, 44, 47, 51, 53, 59, and 61-68 are pending.
Claims 1, 8, 14, 17-18, 21, 23-24, 26, 31-32, 34, 36, 41, 44, 47, 51, 53, 59, and 61-68 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 9 and 13 are under consideration.
Priority
This application is a 371 of PCT/EP2021/056559 filed on March 15, 2021.
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d) of the foreign patent application PCT/EP2020/057108 filed on March 16, 2020, a certified copy of which has been filed with the instant application.
Information Disclosure Statement
Applicant has filed Information Disclosure Statements on September 15, 2022 and March 28, 2025 that have been considered.
The information disclosure statement filed September 15, 2022 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because 37 CFR 1.98(b) requires that each item of information in an IDS be identified properly. Each publication must be identified by publisher, author (if any), title, relevant pages of the publication, and date and place of publication. The date of publication supplied must include at least the month and year of publication, except that the year of publication (without the month) will be accepted if the applicant points out in the information disclosure statement that the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue.
See also MPEP 707.05(e) for electronic documents, including, but not limited to:
(D) reference to the unique Digital Object Identifier (DOI) number, or other unique identification number, if known.
Bibliographic information provided must be at least enough to identify the publication. author, title and date. For books, minimal information includes the author, title, and date. For periodicals, at least the title of the periodical, the volume number, date, and pages should be given.
NPL citations have been lined through for being defective of one or more requirements.
The signed and initialed PTO Forms 1449 are mailed with this action.
Specification
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c).
See amended specification filed November 21, 2025, e.g.:
pg 19, Figures 8-9 legend, “MAGE-A3168-176”;
pg 19, Figure 10 legend, “SSX241-49”;
pg 21, Figure 14 legend, “KRAS-Q61H55-64”;
pg 106, para 1, “KRAS-Q61H55-64”;
pg 110, para 3, “NY-ESO-196-104”;
pg 111, para 1-4, “MAGE-A3168-176”;
pg 112, last para, “NY-ESO-1157-165 SLLMWITQC”; and
pg 113, Example 6, “KRAS-Q61H55-64”.
Each nucleotide and/or amino acid sequence that meets the minimum length threshold must have its SEQ ID NO: in parenthesis next to each occurrence.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
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.
1. Claims 9 and 13 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
With respect to Step 1, the claim is directed to a product, which is a statutory category of invention (Step 1: YES).
Claim 9 recites a TCR polypeptide comprising at least a TCR alpha-chain polypeptide comprising at least one of the CDR sequences of SEQ ID NO:29.
With respect to Step 2A, prong one, the judicial exception, the claim is direct to a product of nature, and thus directed to a judicial exception (Step 2A, prong one: YES).
Bertoletti et al (U.S. 2011/0070208) is considered relevant prior art for having disclosed a TCR alpha-chain polypeptide that is 89% identical to instant SEQ ID NO:29 and a TCR beta-chain polypeptide that is 36% identical to instant SEQ ID NO:30, said alpha- and beta-chains naturally produced in a human in response to exposure to the naturally occurring HBV antigens (e.g. Example 1, [0164], “isolated from fresh blood from a HBV patient”), including HBs370-79 epitope SIVSPFIPLL. See further discussion below per 35 U.S.C. 102(a)(1) rejection.
Similarly, the instant specification discloses said alpha- and beta-chains naturally produced in a human in response to exposure to the naturally occurring tumor antigens (e.g. Figure 3 legend, “post-treatment PBMCs of patient A2-009”), followed by sorting those antigen-reactive T cells and cloning said TCR (e.g. Figure 5 legend, “sorting…. for TCR cloning”).
Thus, instant TCR polypeptide(s) is/are naturally occurring products of nature.
With respect to Step 2A, prong two, the claim does not recite additional elements that integrate the judicial exception into a practical application. The claims do not integrate the judicial exception into a practical application (Step 2A, prong two: NO).
With respect to Step 2B, instantly recited TCR polypeptide(s) do not have markedly different characteristics from what exists in nature. Thus, isolated, but otherwise unchanged TCR polypeptides are not markedly different from what exists in nature.
Claim 13, dependent on Claim 9, recites a nucleic acid encoding the TCR polypeptide. However, those of ordinary skill in the art immediately recognize that it is natural law of cell biology that the patient’s B cells inherently and naturally comprise genomic nucleic acids and mRNA encoding said TCR polypeptide(s). The claimed nucleic acid does not have different functional characteristics as the natural gene and/or mRNA, as it encodes the same polypeptide. Thus, isolated, but otherwise unchanged nucleic acids are not markedly different from what exists in nature. Thus, the claims are not considered to recite additional elements that amount to significantly more than the judicial exception itself (Step 2B: NO).
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(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.
2. Claims 9 and 13 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 9(I) recites the limitation “of claim 1”. There is insufficient antecedent basis for this limitation in the claim because Claim 1 is withdrawn.
Applicant should amend Claim 9 to be complete in and of itself. See, for example, Claim 9(II), (III), and/or (IV).
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
3. Claims 9 and 13 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.
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).
Claim 9 recites at a high level of generality a T cell receptor, or polypeptide chain thereof, which is reactive with a peptide, also recited at a high level of generality.
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 TCR alpha-chain and/or TCR beta-chain antigen binding domains that are to have the functional properties of necessarily and predictably binding the enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed peptides.
The claims are directed to antigen binding domains recited at a high level of generality of TCR alpha-chain and/or TCR beta-chain.
The specification discloses, for example, a TCR alpha-chain SEQ ID NO:29 and a TCR beta-chain of SEQ ID NO:30, each of which is 146 amino acids in length.
20^146 = 9x10^189 structurally undisclosed polypeptides.
The specification discloses the TCR alpha-chain and/or TCR beta-chain polypeptide variants need only be 10% identical to a reference SEQ ID NO (e.g. pg 26).
10% identity to SEQ ID NO:29 or SEQ ID NO:30 allows for 131 amino acid differences.
20^131 = 3x10^170 structurally undisclosed TCR variant polypeptides at least 10% identical.
20^73 = 9x10^94 structurally undisclosed TCR variant polypeptides at least 50% identical
20^58 = 3x10^75 structurally undisclosed TCR variant polypeptides at least 60% identical
20^44 = 2x10^57 structurally undisclosed TCR variant polypeptides at least 70% identical
20^29 = 5x10^37 structurally undisclosed TCR variant polypeptides at least 80% identical
20^15 = 3x10^19 structurally undisclosed TCR variant polypeptides at least 90% identical
(www.calculator.net/exponent-calculator.html; last visited July 14, 2025)
Thus, the claims reasonably encompass:
a) an enormously vast genus of about 9x10^189, 3x10^170, 9x10^94, 3x10^75, 2x10^57, 5x10^37, and/or 3x10^19 structurally undisclosed TCR alpha-chain variant polypeptides that are to have the functional property of binding to an enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed peptides, alone and/or in combination with
b) an enormously vast genus of about 9x10^189, 3x10^170, 9x10^94, 3x10^75, 2x10^57, 5x10^37, and/or 3x10^19 structurally undisclosed TCR beta-chain variant polypeptides that are to have the functional property of binding to an enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed peptides.
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’).
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).
Sela-Culang et al (The structural basis of antibody-antigen recognition, Frontiers in Immunology 4: Article 302, 13 pages, doi: 10.3389/fimmu.2013.00302; available online October 8, 2013) is considered relevant prior art for having taught that while the six CDRs are widely assumed to be responsible for antigen recognition, recent studies and analyses of a growing number of available antibody structures indicate that this assumption is an oversimplification. Some amino acid positions in the CDRs have been shown to never participate in antigen binding, and some amino acid positions in the framework regions, outside the CDRs, often contribute critically to the interaction with antigen (e.g. Abstract).
Rather, some studies indicate that only 20-30% of the CDR residues participate in antigen binding, while the remaining residues are important for maintaining structural conformations of the hypervariable loops (e.g. pg 4, col. 1).
Sela-Culang et al taught that the prior art recognized that simply grafting only the CDRs of a mouse antibody onto a human variable region framework usually results in a significant drop, or a complete loss, of antigen binding. In order to restore antigen binding, one needs to mutate back some of the framework residues to the original mouse antibody (e.g. pg 7, col. 1).
Some of these framework residues that contact and bind the antigen are close in sequence to the CDRs, while other framework residues are far from the CDRs in the primary sequence, but closer proximity in the 3-D structure (e.g. pg 7, col’s 1-2, joining para).
A second category of framework residues that affect antigen binding are those that affect antigen binding indirectly, e.g.:
i) by providing a structural support to the CDRs, enabling them to adopt the right conformation and orientation, shaping the binding site required for antigen binding; or
ii) maintaining the overall structure of the Fv domains by directing the relative orientation of the VH vs VL domains, and thus the orientation of the CDRs relative to each other (e.g. pg 7, col. 2).
Thus, knowing the amino acid sequences of the CDRs, e.g. the CDRs of instant SEQ ID NO’s: 29 and 30, respectively, is not, in and of itself, dispositive of, controlling for, and/or sufficient to describe:
a) the enormously vast genus of about 9x10^189, 3x10^170, 9x10^94, 3x10^75, 2x10^57, 5x10^37, and/or 3x10^19 structurally undisclosed TCR alpha-chain variant polypeptides that are to have the functional property of binding to an enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed peptides, alone and/or in combination with
b) the enormously vast genus of about 9x10^189, 3x10^170, 9x10^94, 3x10^75, 2x10^57, 5x10^37, and/or 3x10^19 structurally undisclosed TCR beta-chain variant polypeptides that are to have the functional property of binding to an enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed peptides.
The amino acid sequences of SEQ ID NO:29 and SEQ ID NO:30, respectively, do not adequately describe the claimed genus of TCR variant molecules because the genus is highly variant in structure and those of ordinary skill in the art recognize that the CDR sequences are not sufficient to necessarily and predictably confer target antigen(s) binding.
As Sela-Culang et al taught, simply grafting only the CDRs of a first antibody variable region onto a second antibody variable region framework usually results in a significant drop, or a complete loss, of antigen binding.
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.
Thus, knowing the identity of the target antigen does not inform the artisan as to the amino acid sequence of the corresponding polypeptide or antibody that can bind to said target 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 enormously vast genus of about 9x10^189, 3x10^170, 9x10^94, 3x10^75, 2x10^57, 5x10^37, and/or 3x10^19 structurally undisclosed TCR alpha-chain variant polypeptides to have the functional property of binding to an enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed peptides, alone and/or in combination with
b) the enormously vast genus of about 9x10^189, 3x10^170, 9x10^94, 3x10^75, 2x10^57, 5x10^37, and/or 3x10^19 structurally undisclosed TCR beta-chain variant polypeptides to have the functional property of binding to an enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed peptides.
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:
a) an enormously vast genus of about 9x10^189, 3x10^170, 9x10^94, 3x10^75, 2x10^57, 5x10^37, and/or 3x10^19 structurally undisclosed TCR alpha-chain variant polypeptides that are to have the functional property of binding to an enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed peptides, alone and/or in combination with
b) an enormously vast genus of about 9x10^189, 3x10^170, 9x10^94, 3x10^75, 2x10^57, 5x10^37, and/or 3x10^19 structurally undisclosed TCR beta-chain variant polypeptides that are to have the functional property of binding to an enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed peptides, 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:
a) enormously vast genus of about 9x10^189, 3x10^170, 9x10^94, 3x10^75, 2x10^57, 5x10^37, and/or 3x10^19 structurally undisclosed TCR alpha-chain variant polypeptides that are to have the functional property of binding to an enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed peptides, alone and/or in combination with
b) enormously vast genus of about 9x10^189, 3x10^170, 9x10^94, 3x10^75, 2x10^57, 5x10^37, and/or 3x10^19 structurally undisclosed TCR beta-chain variant polypeptides that are to have the functional property of binding to an enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed peptides, 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.
Claim 9 recites the phrase “or a variant thereof”.
The instant specification discloses the variant may be as little as 10% to the reference SEQ ID NO (e.g. pg 26, “the degree of similarity or identity….is at least about 10%.....of the entire length of the reference amino acid sequence”).
Claim 9 recites in the alternative (“selected from the group consisting of (I), (II), (III), and (IV), a TCR alpha-chain variant of SEQ ID NO:29 (Claim 9(II)), wherein said TCR alpha-chain need only comprise:
at least one CDR of SEQ ID NO:29, or a variant thereof;
at least two CDRs of SEQ ID NO:29, or variants thereof; or
at least three CDRs of SEQ ID NO:29, or variants thereof.
Instant specification discloses that the TCR alpha-chain SEQ ID NO:29 binds to MAGE-A3(168-176)-specific HLA A*0101-restricted TCR peptide (SEQ ID NO:44; EVDPIGHLY) (e.g. pg 111, last para; pg 114, Table 1, second to last line; pg 119, SEQ ID NO:29).
However, Alten et al (U.S. 2018/0051080) is considered relevant prior art for having disclosed a TCR whose alpha-chain, TCR alpha-chain R4PH3 (e.g. pg 13, Table 1, SEQ ID NO:30), binds to a COL6A3 epitope—not MAGE-A3(168-176)-specific HLA A*0101-restricted TCR peptide (SEQ ID NO:44; EVDPIGHLY) —, wherein said TCR alpha-chain comprises:
i) the same CDR1 amino acid sequence of instant SEQ ID NO:29, to wit, DRGSQS;
ii) the same CDR2 amino acid sequence of instant SEQ ID NO:29, to wit, IYSNGD; and
iii) a CDR3 amino acid sequence that is a variant of (83% identity; 2 mismatches) the CDR3 amino acid sequence instant SEQ ID NO:29 (upper line), as shown below:
CAVWATGNQFYF
||| | ||||||
CAVKA-GNQFYF
The TCR alpha-chain R4PH3 polypeptide is 99% identical (2 mismatches) to instant SEQ ID NO:29 (upper line; CDRs underlined), as shown below:
MKSLRVLLVILWLQLSWVWSQQKEVEQNSGPLSVPEGAIA SLNCTYSDRGSQSFFWYRQY
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
MKSLRVLLVILWLQLSWVWSQQKEVEQNSGPLSVPEGAIA SLNCTYSDRGSQSFFWYRQY
SGKSPELIMFIYSNGDKEDGRFTAQLNKASQYVSLLIRDSQPSDSATYLCAVWATGNQFY
|||||||||||||||||||||||||||||||||||||||||||||||||||| | |||||
SGKSPELIMFIYSNGDKEDGRFTAQLNKASQYVSLLIRDSQPSDSATYLCAVKA-GNQFY
FGTGTSLTVIPNIQNPDPAVYQLRDS
||||||||||||||||||||||||||
FGTGTSLTVIPNIQNPDPAVYQLRDS
The claims fail to recite, and the specification fails to disclose, a first TCR alpha-chain of the enormously vast genus of about 9x10^189, 3x10^170, 9x10^94, 3x10^75, 2x10^57, 5x10^37, and/or 3x10^19 structurally undisclosed TCR alpha-chain variant polypeptides that are to have the functional property of binding to MAGE-A3(168-176)-specific HLA A*0101-restricted TCR peptide (SEQ ID NO:44; EVDPIGHLY), alone and/or in combination with the enormously vast genus of about 9x10^189, 3x10^170, 9x10^94, 3x10^75, 2x10^57, 5x10^37, and/or 3x10^19 structurally undisclosed TCR beta-chain variant polypeptides, respectively, so as to necessarily and predictably bind to MAGE-A3(168-176)-specific HLA A*0101-restricted TCR peptide (SEQ ID NO:44; EVDPIGHLY), for example.
The claims fail to recite, and the specification fails to disclose, a first TCR alpha-chain that is at least 99% identical to instant SEQ ID NO:29 that does not bind MAGE-A3(168-176)-specific HLA A*0101-restricted TCR peptide (SEQ ID NO:44; EVDPIGHLY), however, when paired with the enormously vast genus of about 9x10^189, 3x10^170, 9x10^94, 3x10^75, 2x10^57, 5x10^37, and/or 3x10^19 structurally undisclosed TCR beta-chain variant polypeptides will now, necessarily and predictably have the functional property of binding to MAGE-A3(168-176)-specific HLA A*0101-restricted TCR peptide (SEQ ID NO:44; EVDPIGHLY), as opposed to a second TCR alpha-chain that is at least 99% identical to instant SEQ ID NO:29 that does bind MAGE-A3(168-176)-specific HLA A*0101-restricted TCR peptide (SEQ ID NO:44; EVDPIGHLY) when paired with the enormously vast genus of about 9x10^189, 3x10^170, 9x10^94, 3x10^75, 2x10^57, 5x10^37, and/or 3x10^19 structurally undisclosed TCR beta-chain variant polypeptides will now, necessarily and predictably have the functional property of binding to MAGE-A3(168-176)-specific HLA A*0101-restricted TCR peptide (SEQ ID NO:44; EVDPIGHLY), for example.
Claim 9 recites in the alternative (“selected from the group consisting of (I), (II), (III), and (IV), a TCR beta-chain variant of SEQ ID NO:30 (Claim 9(III)), wherein said TCR beta-chain need only comprise:
at least one CDR of SEQ ID NO:30, or a variant thereof;
at least two CDRs of SEQ ID NO:30, or variants thereof; or
at least three CDRs of SEQ ID NO:30, or variants thereof.
Instant specification discloses that the TCR beta-chain SEQ ID NO:30 binds to MAGE-A3(168-176)-specific HLA A*0101-restricted TCR peptide (SEQ ID NO:44; EVDPIGHLY) (e.g. pg 111, last para; pg 114, Table 1, second to last line; pg 119, SEQ ID NO:30).
Alten et al is considered relevant prior art for having also disclosed a TCR whose beta-chain, TCR beta-chain R37P1C9 (e.g. pg 25, Table 1, SEQ ID NO:60), binds to a COL6A3 epitope—not MAGE-A3(168-176)-specific HLA A*0101-restricted TCR peptide (SEQ ID NO:44; EVDPIGHLY) —, wherein said TCR beta-chain comprises:
i) the same CDR1 amino acid sequence of instant SEQ ID NO:30, to wit, LNHNV;
ii) the same CDR2 amino acid sequence of instant SEQ ID NO:30, to wit, YYDKDF; and
iii) a CDR3 amino acid sequence that is a variant of (46% identity) the CDR3 amino acid sequence instant SEQ ID NO:30 (upper line), as shown below:
CATSFDRGYEQ-YF
|||| |: :|
CATSSGETNEKLFF
The TCR beta-chain polypeptide is 90% identical (15 mismatches) to instant SEQ ID NO:30 (upper line; CDRs underlined), as shown below:
MGPGLLHWMALCLLGTGHGDAMVIQNPRYQVTQFGKPVTLSCSQTLNHNVMYWYQQKSSQ
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
MGPGLLHWMALCLLGTGHGDAMVIQNPRYQVTQFGKPVTLSCSQTLNHNVMYWYQQKSSQ
APKLLFHYYDKDFNNEADTPDNFQSRRPNTSFCFLDIRSPGLGDTAMYLCATSFDRGYEQ
|||||||||||||||||||||||||||||||||||||||||||| |||||||| |:
APKLLFHYYDKDFNNEADTPDNFQSRRPNTSFCFLDIRSPGLGDAAMYLCATSSGETNEK
-YFGPGTRLTVTEDLKNVFPPEVAVFE
:|| ||:|:| ||| ||||||||||
LFFGSGTQLSVLEDLNKVFPPEVAVFE
Thus, the prior art clearly evidences TCR alpha- and/or beta-chains that fulfill the instantly recited structural requirements, but fail to fulfill the disclosed functional properties.
The claims fail to recite, and the specification fails to disclose, a first TCR beta-chain that is at least 90% identical to instant SEQ ID NO:30 that does not bind MAGE-A3(168-176)-specific HLA A*0101-restricted TCR peptide (SEQ ID NO:44; EVDPIGHLY), however, when paired with the enormously vast genus of about 9x10^189, 3x10^170, 9x10^94, 3x10^75, 2x10^57, 5x10^37, and/or 3x10^19 structurally undisclosed TCR alpha-chain variant polypeptides will now, necessarily and predictably have the functional property of binding to MAGE-A3(168-176)-specific HLA A*0101-restricted TCR peptide (SEQ ID NO:44; EVDPIGHLY), as opposed to a second TCR beta-chain that is at least 90% identical to instant SEQ ID NO:30 that does bind MAGE-A3(168-176)-specific HLA A*0101-restricted TCR peptide (SEQ ID NO:44; EVDPIGHLY) when paired with the enormously vast genus of about 9x10^189, 3x10^170, 9x10^94, 3x10^75, 2x10^57, 5x10^37, and/or 3x10^19 structurally undisclosed TCR alpha-chain variant polypeptides will now, necessarily and predictably have the functional property of binding to MAGE-A3(168-176)-specific HLA A*0101-restricted TCR peptide (SEQ ID NO:44; EVDPIGHLY), for example.
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 antigen peptide is one of an enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed peptides does not tell you anything at all about:
a) the enormously vast genus of about 9x10^189, 3x10^170, 9x10^94, 3x10^75, 2x10^57, 5x10^37, and/or 3x10^19 structurally undisclosed TCR alpha-chain variant polypeptides that are to have the functional property of binding to said enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed peptides, alone and/or in combination with
b) the enormously vast genus of about 9x10^189, 3x10^170, 9x10^94, 3x10^75, 2x10^57, 5x10^37, and/or 3x10^19 structurally undisclosed TCR beta-chain variant polypeptides that are to have the functional property of binding to said enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed peptides, respectively.
Similarly, knowing that the initial TCR alpha-chain and/or TCR beta-chain variant polypeptides is/are 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 9x10^189, 3x10^170, 9x10^94, 3x10^75, 2x10^57, 5x10^37, and/or 3x10^19 structurally undisclosed TCR alpha-chain and TCR beta-chain variant polypeptides, respectively, that are to have the functional property of binding to said enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed peptides, 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:
an enormously vast genus of about 9x10^189, 3x10^170, 9x10^94, 3x10^75, 2x10^57, 5x10^37, and/or 3x10^19 structurally undisclosed TCR alpha-chain and TCR beta-chain variant polypeptides, respectively, that are to have the functional property of binding to said enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed peptides, 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.
The single TCR alpha-chain amino acid sequence SEQ ID NO:29 species, when paired with the single TCR beta-chain amino acid sequence SEQ ID NO:30 species, that binds to the single MAGE-A3(168-176)-specific HLA A*0101-restricted TCR peptide (SEQ ID NO:44; EVDPIGHLY) species is not representative of the claimed enormously vast genus of structurally and functionally undisclosed TCR alpha-chains, TCR beta-chains, and target peptides, respectively.
The single TCR alpha-chain amino acid sequence SEQ ID NO:29 species is not representative of the claimed enormously vast genus of about 9x10^189, 3x10^170, 9x10^94, 3x10^75, 2x10^57, 5x10^37, and/or 3x10^19 structurally undisclosed TCR alpha-chains.
The single TCR beta-chain amino acid sequence SEQ ID NO:30 species is not representative of the claimed enormously vast genus of about 9x10^189, 3x10^170, 9x10^94, 3x10^75, 2x10^57, 5x10^37, and/or 3x10^19 structurally undisclosed TCR alpha-chains.
The single MAGE-A3(168-176)-specific HLA A*0101-restricted TCR peptide (SEQ ID NO:44; EVDPIGHLY) species is not representative of the claimed enormously vast genus of about 1x10^65, 1x10^52, 1x10^39, 1x10^26, and/or 1x10^13 structurally undisclosed peptides.
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 Claim 13 is included in the basis of the rejection because they encompass the embodiments of Claim 9, but they do not correct the primary deficiencies of Claim 9.
4. Claims 9 and 13 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 Examiner incorporates herein the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description rejection.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
5. Claim(s) 9 and 13 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bertoletti et al (U.S. 2011/0070208).
Claim 9 recites the phrase “or a variant thereof”.
The instant specification discloses the variant may be as little as 10% to the reference SEQ ID NO (e.g. pg 26, “the degree of similarity or identity….is at least about 10%.....of the entire length of the reference amino acid sequence”).
With respect to Claim 9, Bertoletti et al is considered relevant prior art for having disclosed a TCR whose alpha-chain, TCR alpha 12 (e.g. pg 15, Table 2, TCR alpha 12), binds to an HBV epitope, wherein said TCR alpha-chain comprises:
i) the same CDR1 amino acid sequence of instant SEQ ID NO:29, to wit, DRGSQS;
ii) the same CDR2 amino acid sequence of instant SEQ ID NO:29, to wit, IYSNGD; and
iii) a CDR3 amino acid sequence that is a variant of (25% identity) the CDR3 amino acid sequence instant SEQ ID NO:29 (upper line), as shown below:
CAV-WATGNQFYF
||| || |
CAVNLYAGNMLTF
The TCR alpha 12 polypeptide is 89% identical to instant SEQ ID NO:29 (upper line; CDRs underlined), as shown below:
MKSLRVLLVILWLQLSWVWSQQKEVEQNSGPLSVPEGAIA SLNCTYSDRGSQSFFWYRQY
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
MKSLRVLLVILWLQLSWVWSQQKEVEQNSGPLSVPEGAIA SLNCTYSDRGSQSFFWYRQY
SGKSPELIMFIYSNGDKEDGRFTAQLNKASQYVSLLIRDSQPSDSATYLCAV-WATGNQF
|||||||||||||||||||||||||||||||||||||||||||||||||||| ||
SGKSPELIMFIYSNGDKEDGRFTAQLNKASQYVSLLIRDSQPSDSATYLCAVNLYAGNML
YFGTGTSLTVIPNIQNPDPAVYQLRDS
|| || | | |:||||||||||||||
TFGGGTRLMVKPHIQNPDPAVYQLRDS
Bertoletti et al disclosed a TCR whose beta-chain, TCR beta 7.8, binds to an HBV epitope, said TCR beta-chain comprises a CDR3 amino acid sequence that is a variant of (37% identity) the CDR3 amino acid sequence instant SEQ ID NO:30 (upper line), as shown below:
CATSFDRGYE-QYF
||:| | | : |:|
CASSSDFGNQPQHF
The TCR beta 7.8 polypeptide is 36% identical to instant SEQ ID NO:30 (upper line; CDRs underlined), as shown below:
MGPGLLHWMALCLLGTGHGDAMVIQNPRYQVTQFGKPVTLSCSQTLNHNVMYWYQQKSSQ
|| || | | ||| | | | |:|||:| : |: | | | | ::|||| |
MGTRLLCWW-LGFLGTDHTGAGVSQSPRYKVAKRGQDVALRCDPISGHVSLFWYQQALGQ
APKLLFHYYDKDFNNEAD------TPDNFQSRRPNTSFCFLDIRSPGLGDTAMYLCATSF
|: | : | ||| | | : || | | |: |:|:||||:|
GPEFLTY-----FQNEAQLDKSGLPSDRFFAERPEGSVSTLKIQRTQQEDSAVYLCASSS
DRGYE-QYFGPGTRLTVTEDLKNVFPPEVAVFE
| | : |:|| ||||:: ||| ||||||||||
DFGNQPQHFGDGTRLSILEDLNKVFPPEVAVFE
With respect to Claim 9(I),
"Products of identical chemical composition can not have mutual exclusive properties." A compound and its properties are inseparable (In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963)). Any properties exhibited by or benefits from are not given any patentable weight over the prior art provided the composition is inherent. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the disclosed properties are necessarily present. In re Spada, 911 F.2d 705,709, 15 USPQ 1655, 1658 (Fed. Cir. 1990). See MPEP §2112.01. The burden is shifted to the applicant to show that the prior art product does not inherently possess the same properties as the instantly claimed product.
To the extent Applicant argues that the TCR alpha-chain and/or TCR beta-chain does not bind the peptide(s), or variants thereof, per embodiment Claim 9(I), then something must change.
See above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
With respect to Claim 13, Bertoletti et al disclosed a nucleic acid encoding said TCR polypeptide (e.g. Abstract).
Thus, Bertoletti et al anticipate the claims.
6. Claim(s) 9 and 13 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Alten et al (U.S. 2018/0051080).
Claim 9 recites the phrase “or a variant thereof”.
The instant specification discloses the variant may be as little as 10% to the reference SEQ ID NO (e.g. pg 26, “the degree of similarity or identity….is at least about 10%.....of the entire length of the reference amino acid sequence”).
With respect to Claim 9, Alten et al is considered relevant prior art for having disclosed a TCR whose alpha-chain, TCR alpha-chain R4PH3 (e.g. pg 13, Table 1, SEQ ID NO:30), binds to an COL6A3 epitope, wherein said TCR alpha-chain comprises:
i) the same CDR1 amino acid sequence of instant SEQ ID NO:29, to wit, DRGSQS;
ii) the same CDR2 amino acid sequence of instant SEQ ID NO:29, to wit, IYSNGD; and
iii) a CDR3 amino acid sequence that is a variant of (83% identity) the CDR3 amino acid sequence instant SEQ ID NO:29 (upper line), as shown below:
CAVWATGNQFYF
||| | ||||||
CAVKA-GNQFYF
The TCR alpha 12 polypeptide is 99% identical (2 mismatches) to instant SEQ ID NO:29 (upper line; CDRs underlined), as shown below:
MKSLRVLLVILWLQLSWVWSQQKEVEQNSGPLSVPEGAIA SLNCTYSDRGSQSFFWYRQY
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
MKSLRVLLVILWLQLSWVWSQQKEVEQNSGPLSVPEGAIA SLNCTYSDRGSQSFFWYRQY
SGKSPELIMFIYSNGDKEDGRFTAQLNKASQYVSLLIRDSQPSDSATYLCAVWATGNQFY
|||||||||||||||||||||||||||||||||||||||||||||||||||| | |||||
SGKSPELIMFIYSNGDKEDGRFTAQLNKASQYVSLLIRDSQPSDSATYLCAVKA-GNQFY
FGTGTSLTVIPNIQNPDPAVYQLRDS
||||||||||||||||||||||||||
FGTGTSLTVIPNIQNPDPAVYQLRDS
Alten et al is considered relevant prior art for having disclosed a TCR whose beta-chain, TCR beta-chain R37P1C9 (e.g. pg 25, Table 1, SEQ ID NO:60), binds to an COL6A3 epitope, wherein said TCR beta-chain comprises:
i) the same CDR1 amino acid sequence of instant SEQ ID NO:30, to wit, LNHNV;
ii) the same CDR2 amino acid sequence of instant SEQ ID NO:30, to wit, YYDKDF; and
iii) a CDR3 amino acid sequence that is a variant of (46% identity) the CDR3 amino acid sequence instant SEQ ID NO:30 (upper line), as shown below:
CATSFDRGYEQ-YF
|||| |: :|
CATSSGETNEKLFF
The TCR beta-chain polypeptide is 90% identical (15 mismatches) to instant SEQ ID NO:30 (upper line; CDRs underlined), as shown below:
MGPGLLHWMALCLLGTGHGDAMVIQNPRYQVTQFGKPVTLSCSQTLNHNVMYWYQQKSSQ
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
MGPGLLHWMALCLLGTGHGDAMVIQNPRYQVTQFGKPVTLSCSQTLNHNVMYWYQQKSSQ
APKLLFHYYDKDFNNEADTPDNFQSRRPNTSFCFLDIRSPGLGDTAMYLCATSFDRGYEQ
|||||||||||||||||||||||||||||||||||||||||||| |||||||| |:
APKLLFHYYDKDFNNEADTPDNFQSRRPNTSFCFLDIRSPGLGDAAMYLCATSSGETNEK
-YFGPGTRLTVTEDLKNVFPPEVAVFE
:|| ||:|:| ||| ||||||||||
LFFGSGTQLSVLEDLNKVFPPEVAVFE
With respect to Claim 9(I),
"Products of identical chemical composition can not have mutual exclusive properties." A compound and its properties are inseparable (In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963)). Any properties exhibited by or benefits from are not given any patentable weight over the prior art provided the composition is inherent. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the disclosed properties are necessarily present. In re Spada, 911 F.2d 705,709, 15 USPQ 1655, 1658 (Fed. Cir. 1990). See MPEP §2112.01. The burden is shifted to the applicant to show that the prior art product does not inherently possess the same properties as the instantly claimed product.
To the extent Applicant argues that the TCR alpha-chain and/or TCR beta-chain does not bind the peptide(s), or variants thereof, per embodiment Claim 9(I), then something must change.
See above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
With respect to Claim 13, Alten et al disclosed a nucleic acid encoding said TCR polypeptide (e.g. [0054-57]).
Thus, Alten et al anticipate the claims.
7. Claim(s) 9 and 13 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Alten et al (U.S. 2018/0161396).
Claim 9 recites the phrase “or a variant thereof”.
The instant specification discloses the variant may be as little as 10% to the reference SEQ ID NO (e.g. pg 26, “the degree of similarity or identity….is at least about 10%.....of the entire length of the reference amino acid sequence”).
With respect to Claim 9, Alten et al is considered relevant prior art for having disclosed a TCR whose beta-chain, TCR beta R37P1C9, binds to a MAGEA1 epitope (e.g. pg 25, Table 1), wherein said TCR beta-chain comprises:
i) the same CDR1 amino acid sequence of instant SEQ ID NO:30, to wit, LNHNV;
ii) the same CDR2 amino acid sequence of instant SEQ ID NO:30, to wit, YYDKDF; and
iii) a CDR3 amino acid sequence that is a variant of (35% identity) the CDR3 amino acid sequence instant SEQ ID NO:30 (upper line), as shown below:
CATSFDRGYEQYF
|||| |: |
CATSSGETNEKLF
The TCR beta R37P1C9 polypeptide is 80% identical to instant SEQ ID NO:30 (upper line; CDRs underlined), as shown below:
MGPGLLHWMALCLLGTGHGDAMVIQNPRYQVTQFGKPVTLSCSQTLNHNVMYWYQQKSSQ
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
MGPGLLHWMALCLLGTGHGDAMVIQNPRYQVTQFGKPVTLSCSQTLNHNVMYWYQQKSSQ
APKLLFHYYDKDFNNEADTPDNFQSRRPNTSFCFLDIRSPGLGDTAMYLCATSFDRGYEQ
|||||||||||||||||||||||||||||||||||||||||||| |||||||| |:
APKLLFHYYDKDFNNEADTPDNFQSRRPNTSFCFLDIRSPGLGDAAMYLCATSSGETNEK
-YFGPGTRLTV
:|| ||:|:|
LFFGSGTQLSV
With respect to Claim 9(I),
"Products of identical chemical composition can not have mutual exclusive properties." A compound and its properties are inseparable (In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963)). Any properties exhibited by or benefits from are not given any patentable weight over the prior art provided the composition is inherent. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the disclosed properties are necessarily present. In re Spada, 911 F.2d 705,709, 15 USPQ 1655, 1658 (Fed. Cir. 1990). See MPEP §2112.01. The burden is shifted to the applicant to show that the prior art product does not inherently possess the same properties as the instantly claimed product.
To the extent Applicant argues that the TCR alpha-chain and/or TCR beta-chain does not bind the peptide(s), or variants thereof, per embodiment Claim 9(I), then something must change.
See above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
With respect to Claim 13, Alten et al disclosed a nucleic acid encoding said TCR polypeptide (e.g. Abstract).
Thus, Alten et al anticipate the claims.
8. Claim(s) 9 and 13 is/are rejected under 35 U.S.C. 102(a)(1) and/or 35 U.S.C. 102(a)(2) as being anticipated by Yee et al (WO 19/204683; filed April 19, 2019; priority to April 19, 2018).
Claim 9 recites the phrase “or a variant thereof”.
The instant specification discloses the variant may be as little as 10% to the reference SEQ ID NO (e.g. pg 26, “the degree of similarity or identity….is at least about 10%.....of the entire length of the reference amino acid sequence”).
With respect to Claim 9, Yee et al is considered relevant prior art for having disclosed a TCR whose beta-chain, TCR beta TRBV15*02F, binds to a MAGE-B2 epitope (e.g. pg 13), wherein said TCR beta-chain comprises:
i) the same CDR1 amino acid sequence of instant SEQ ID NO:30, to wit, LNHNV;
ii) the same CDR2 amino acid sequence of instant SEQ ID NO:30, to wit, YYDKDF; and
iii) a CDR3 amino acid sequence that is a variant of (39% identity) the CDR3 amino acid sequence instant SEQ ID NO:30 (upper line), as shown below:
CATSFDRGY-EQYF
|||| | ||:|
CATSRGGRYNEQFF
The TCR beta TRBV15*02F polypeptide is 93% identical to instant SEQ ID NO:30 (upper line; CDRs underlined), as shown below:
MGPGLLHWMALCLLGTGHGDAMVIQNPRYQVTQFGKPVTLSCSQTLNHNVMYWYQQKSSQ
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
MGPGLLHWMALCLLGTGHGDAMVIQNPRYQVTQFGKPVTLSCSQTLNHNVMYWYQQKSSQ
APKLLFHYYDKDFNNEADTPDNFQSRRPNTSFCFLDIRSPGLGDTAMYLCATSFDRGY-E
|||||||||||||||||||||||||||||||||||||||||||| |||||||| | |
APKLLFHYYDKDFNNEADTPDNFQSRRPNTSFCFLDIRSPGLGDAAMYLCATSRGGRYNE
QYFGPGTRLTVTEDLKNVFPPEVAVFE
|:||||||||| |||||||||||||||
QFFGPGTRLTVLEDLKNVFPPEVAVFE
With respect to Claim 9(I),
"Products of identical chemical composition can not have mutual exclusive properties." A compound and its properties are inseparable (In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963)). Any properties exhibited by or benefits from are not given any patentable weight over the prior art provided the composition is inherent. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the disclosed properties are necessarily present. In re Spada, 911 F.2d 705,709, 15 USPQ 1655, 1658 (Fed. Cir. 1990). See MPEP §2112.01. The burden is shifted to the applicant to show that the prior art product does not inherently possess the same properties as the instantly claimed product.
To the extent Applicant argues that the TCR alpha-chain and/or TCR beta-chain does not bind the peptide(s), or variants thereof, per embodiment Claim 9(I), then something must change.
See above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
With respect to Claim 13, Yee et al disclosed a nucleic acid encoding said TCR polypeptide (e.g. [0014]).
Thus, Yee et al anticipate the claims.
9. Claim(s) 9 and 13 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Robbins et al (U.S. 2014/0378389).
With respect to Claim 9, Robbins et al is considered relevant prior art for having disclosed a TCR whose beta-chain, TCR beta 13-18 (SEQ ID NO:25), binds to a MAGE-A3 epitope (e.g. [0031], MAGE-A3(168-176) peptide EVDPIGHLY; Example 1, [0117]; Example 2, [0120]), wherein said TCR beta-chain comprises:
i) the same CDR1 amino acid sequence of instant SEQ ID NO:30, to wit, LNHNV;
ii) the same CDR2 amino acid sequence of instant SEQ ID NO:30, to wit, YYDKDF; and
iii) a CDR3 amino acid sequence that is a variant of (92% identity; 1 mismatch) the CDR3 amino acid sequence instant SEQ ID NO:30 (upper line), as shown below:
CATSFDRGYEQYF
||||:||||||||
CATSWDRGYEQYF
The TCR beta TCR beta-chain 13-18 polypeptide binds to the same target antigen (e.g. [0031], MAGE-A3(168-176) peptide EVDPIGHLY) as the instant TCR beta-chain, and is 99% identical (2 mismatches) to instant SEQ ID NO:30 (upper line; CDRs underlined), as shown below:
MGPGLLHWMALCLLGTGHGDAMVIQNPRYQVTQFGKPVTLSCSQTLNHNVMYWYQQKSSQ 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
MGPGLLHWMALCLLGTGHGDAMVIQNPRYQVTQFGKPVTLSCSQTLNHNVMYWYQQKSSQ 60
APKLLFHYYDKDFNNEADTPDNFQSRRPNTSFCFLDIRSPGLGDTAMYLCATSFDRGYEQ 120
|||||||||||||||||||||||||||||||||||||||||||| ||||||||:||||||
APKLLFHYYDKDFNNEADTPDNFQSRRPNTSFCFLDIRSPGLGDAAMYLCATSWDRGYEQ 120
YFGPGTRLTVTEDLKNVFPPEVAVFE
||||||||||||||||||||||||||
YFGPGTRLTVTEDLKNVFPPEVAVFE
With respect to Claim 9(I),
"Products of identical chemical composition can not have mutual exclusive properties." A compound and its properties are inseparable (In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963)). Any properties exhibited by or benefits from are not given any patentable weight over the prior art provided the composition is inherent. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the disclosed properties are necessarily present. In re Spada, 911 F.2d 705,709, 15 USPQ 1655, 1658 (Fed. Cir. 1990). See MPEP §2112.01. The burden is shifted to the applicant to show that the prior art product does not inherently possess the same properties as the instantly claimed product.
To the extent Applicant argues that the TCR alpha-chain and/or TCR beta-chain does not bind the peptide(s), or variants thereof, per embodiment Claim 9(I), then something must change.
See above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
With respect to Claim 13, Robbins et al disclosed a nucleic acid encoding said TCR polypeptide (e.g. [0063, 67-68]).
Thus, Robbins et al anticipate the claims.
Citation of Relevant Prior Art
10. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
GenBank F3480 (TCR alpha-chain, clone TIL 5, 1999) is considered relevant prior art for having taught a TCR alpha-chain that binds to melanoma tumor antigen, said TCR alpha-chain comprises a CDR3 motif whose amino acid is 92% identical (1 mismatch) to the TCR alpha-chain CDR3 motif of instant SEQ ID NO:29 (upper line), as shown below:
CAVWATGNQFYF
||| ||||||||
CAVGATGNQFYF
GenBank AVK78626 (TCR beta-chain, partial, 2018) is considered relevant prior art for having taught a TCR beta-chain that binds to melanoma tumor antigen, said TCR beta-chain comprises a CDR3 motif whose amino acid is 84% identical (2 mismatches) to the TCR beta-chain CDR3 motif of instant SEQ ID NO:30 (upper line), as shown below:
CATSFDRGYEQYF
|||: ||||||||
CATTRDRGYEQYF
Conclusion
11. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEVIN K. HILL whose telephone number is (571)272-8036. The examiner can normally be reached 12pm-8pm EST.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638