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
1. Applicant’s amendment filed 2/8/24 is acknowledged and has been entered.
2. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
3. The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which Applicant may become aware in the specification.
4. 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.
5. Claims 1, 2, 4, 19, 20, 23-27 and 29 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
Claim interpretation: The specification discloses that the wild type KRAS peptide corresponds to the sequence of SEQ ID NO: 3 (KLVVVGAGGV) ([52]). As the specification discloses at [0052] that mutant G12 peptides comprise G12 variants of the wild type peptide as well as overlapping sequences (see for example SEQ ID NO: 7 and 8), the said limitation encompasses any HLA binding peptide comprising a subsequence of a intracellular portion of an oncogenic KRAS protein comprising a G12 mutation. The limitation “wherein the molecules does not specifically bind to the peptide in its wild-type form” recited in instant base claim 1 is being interpreted as either nominal peptide or peptide bound to the same HLA as is the mutant peptide (see indefiniteness rejection above in this office action).
An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it"). "Compliance with the written description requirement is essentially a fact-based inquiry that will ‘necessarily vary depending on the nature of the invention claimed.' " Enzo Biochem, 323 F.3d at 963, 63 USPQ2d at 1612. An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. See MPEP 2163 I.A.
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613 (quoting the Written Description Guidelines, 66 Fed. Reg. at 1106, n. 49, stating that "if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function".). "Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function." See MPEP 2163 II.3.
Applicant has broadly claimed:
Aan isolated molecule comprising an antibody variable region which specifically binds to a complex of an HLA molecule and a peptide which is a portion of a protein, wherein the peptide comprises a mutant residue, and wherein the mutant residue is in an intracellular epitope of the protein, wherein the molecule does not specifically bind to the HLA molecule when the HLA molecule is not in said complex, wherein the molecule does not specifically bind to the peptide in its wild-type form, and wherein the protein is an oncogenic KRAS protein comprising a G12 mutation (as recited in instant base claim 1), and including wherein:
the complex further comprises a b2m molecule (claim 2);
the molecule comprises a Fab (claim 4);
the oncogenic protein has a G12V mutation (claim 19) and wherein the oncogenic protein has a G12V mutation, wherein the peptide comprising a mutant residue is SEQ ID NO: 4 (claim 20);
the isolated molecule does not bind to the peptide when it is not in the complex (claim 23);
the HLA molecule is HLA-A2 (claim 24);
the HLA molecule is HLA-A3 (claim 25);
the isolated molecule further comprises a therapeutic agent (claim 27), or
the isolated molecule further comprises an scFv that specifically binds to CD3 (claim 29), including the limitations of the dependent claims.
As such the isolated molecule comprising an antibody variable region is claimed functionally by its ability to bind to a complex of a generic HLA molecule and a peptide that is a portion of a protein, the peptide comprising a mutant residue, and wherein the mutant residue is in an intracellular epitope of the oncogenic protein KRAS comprising a generic mutation at position 12 (i.e., “G12”) (as is recited in instant base claim 1) or a specific G12 mutation “G12V” (dependent claim 20), including wherein the HLA molecule may be HLA-2 or HLA-3 (claims 24 and 25, respectively).
The specification does not disclose a representative number of species of such isolated molecule comprising an antibody variable region that binds to an HLA molecule and KRAS G12 mutant peptide, nor sufficient relevant identifying characteristics in the form of structure or functional characteristics coupled with a known or disclosed correlation between structure and function.
This is because a functional recitation such as a binding specificity (to an HLA/peptide complex), nor a general structure such as an antibody variable region, including in a Fab (claim 4) or other antibody variable region, does not provide adequate written description for the amino acid sequence(s) of the antibody variable region. The amino acid sequences cannot be envisioned a priori by a binding specificity. There is no structure/function relationship for the amino acid sequence of an antibody and the antigen to which it binds.
As Applicant is undoubtedly aware, recent court decisions in the biotechnology arena have highlighted the issue with defining binding members strictly using functional terms as can be readily seen in both AbbVie Deutschland GmbH v. Janssen Biotech. Inc. 759 F.3d 1285 (Fed. Cir. 2014) and Amgen v. Sanofi. (Fed Cir, 2017-1480. 10/5/2017).
Indeed, in Amgen the court indicates that that it is improper to allow patentees to claim a binding molecule by describing something that is not the invention, i.e., the structure to which it binds, as knowledge of the chemical structure of the thing being bound does not give the required kind of structure-identifying information about the thing being claimed.
The art recognizes that the sequence of an antibody that binds to a same protein or other target antigen, a same epitope an antigen, or to overlapping epitopes of an antigen is broad and structurally diverse (i.e., the amino acid sequences of the cognate binding portions (or CDRs) are diverse). There is no structure/function relationship.
As pertains to structure/function, the following evidentiary references teach the large structural diversity inherent in different antibodies that bind to a same or overlapping epitopes of an antigen.
Poosarla et al. (Biotechn. Bioeng., 2017, 114(6): 1331-1342) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes…in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Khan and Salunke (J. Immunol, 2014, 192: 5398-5405) teach that two structurally diverse germline mAbs recognizing overlapping epitopes of the same short peptide do so in different topologies, the said antibodies possessing entirely different CDR sequences. Said reference teaches that unrelated mAbs structurally adjust to recognize an antigen, indicating that the primary B cell response is composed of BCRs having a high degree of structural adaptability. Said reference also teaches that the common epitope(s) also adopt distinct conformations when bound to different mAbs, with the higher degree of structural plasticity inherent to the mAbs. Said reference further teaches “It has been shown that both the framework region and the CDRs have a considerable amount of inherent conformational plasticity…Therefore, it is not surprising that distinct germline Abs recognize the same epitope by rearranging the CDR conformations. This may well have implications of Ag specificity beyond the naïve BCR repertoire, because Kaji et al….have shown in a recent report that the B cell memory can contain both germline-encoded and somatically mutated BCRs.” (See entire reference).
Lloyd et al. (Protein Engineering, Eng. Design & Selection, 2009, 22(3): 159-168) teach that a large majority of VH/VL germline gene segments are used in the antibody response to an antigen, even when the antibodies were selected by antigen binding. Said reference further teaches that in their studies, of the 841 unselected and 5,044 selected antibodies sequenced, all but one of the 49 functional VH gene segments was observed, and that there are on average about 120 different antibodies generated per antigen. Said reference also teaches that a wide variety of VH and VL pairings further increase diversity. (See entire reference.)
Edwards et al. (JMB, 2003, 334: 103-118) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences, and representative of almost the entire extensive heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lamda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well.
Nor does the specification disclose a representative number of such isolated molecules comprising an antibody variable region that binds to a complex of an HLA molecule and a KRAS G12 mutant peptide. The specification discloses two antibody clones that bind to the HLA-A2/G12V KRAS peptide complex and four affinity matured variants thereof.
The specification discloses that a wild type KRAS peptide corresponds to SEQ ID NO: 3 (KLVVVGAGGV), a KRAS “G12” mutant peptide corresponding to the sequence of instantly recited SEQ ID NO: 4 (KLVVVGAVGV) (recited in claim 20) and one mutant KRAS “G12” peptide corresponding to SEQ ID NO: 7 (VVGAVGVGK) (not recited) that is predicted to bind to HLA-A2 or HLA-A3, respectively. The specification further discloses a mutant KRAS G12C peptide corresponding to SEQ ID NO: 5 (KLVVVGACGV) (predicted to bind to HLA-A2), a mutant KRAS G12D peptide corresponding to SEQ ID NO: 6 (KLVVGADGV) predicted to bind to HLA-A2, and a mutant KRAS G12C peptide (VVGACGVGK) predicted to bind to HLA-A3 ([52], [74]).
The specification discloses that eight clones were identified as having higher affinity to HLA-A2/KRAS G12V than a complex of HLA-A2 with the wild type peptide, and one clone D10-7 was chosen for further characterization ([58], [77]). D10 scFv did not bind to complexes of HLA-A2 or HLA-A3 with wild type peptide or KRAS G12C or G12D peptides, nor did it bind to KRAS peptides when not complexed with HLA proteins ([78]). The specification discloses that D10 scFv was estimated to be 49 nM, so affinity maturation was performed (with one candidate still differentiating between mutant G12V peptide and wild type peptide, but acquiring a new binding specificity to G12C/HLA-A2 complexes) ([79]). The specification discloses that the D10 scFv sequence was grafted onto the constant region of humanized antibody trastuzumab, with the antibody retaining high specificity and low dissociation rate constant observed with the D10 scFv antibody fragment ([83]). The D10 scFv sequence corresponds to SEQ ID NO: 37 ([58]), while an affinity matured variant of D10 corresponds to SEQ ID NO: 38 ([58]).
The specification discloses another example of a clone (“F10”) specific for KRAS G12V/HLA-A2 (SEQ ID NO: 21) and affinity matured clones thereof (SEQ ID NO: 22-24) (Examples 9 and 10, respectively).
As a further issue in addition to an antibody sequence not being described by its functional property of binding specificity, the art recognizes that there are over 25,000 different HLA class I molecules, as well as over 10,000 different HLA class II molecules (see evidentiary reference HLA Nomenclature, 2023, 2 pages). As indicated above, the specification discloses that the G12 KRAS peptide may include additional amino acid residues as compared to the wild type KRAS peptide and besides the G12 mutation, it may also comprise mutations at other positions in the peptide. In the more generically recited claims, the identity of the binding specificity (i.e., the particular HLA/peptide complex) is not even recited (and the specification does not disclose which other HLA molecules and corresponding G12 mutant KRAS peptides are included in the genus of antigens, i.e, which HLA molecules can bind to which if any G12 mutant KRAS peptides).
With further regard to dependent claim 2, said claim recites “wherein said complex further comprises a b-2-microglobulin molecule. Thus, the antigenic target recited in instant base claim 1 (and its other dependent claims) need not comprise b2m. The specification, nor the art disclose which if any HLA heavy chains with out b2m can form a complex with a functioning peptide binding site to bind a KRAS G12 mutant peptide. The art was aware that the typical complex is a ternary complex of HLA heavy chain, b2m and peptide.
One of skill in the art was aware that HLA class I molecules are extremely polymorphic, and the polymorphisms primarily reside in the area of the peptide binding groove formed by the alpha 1 and alpha 2 domains of the HLA class I heavy chain [as is evidenced by Liu et al. (MHC Complex: Interaction with Peptides. IN: eLS. John Wiley & Sons, Ltd: Chichester, DOI: 10.1002/9780470015902.a0000922.pub2, 2011, pages 1-12, see entire reference, e.g., Overall Structure and Peptide Binding Groove sections). This pertains to the lack of a structure/function relationship for a particular HLA molecule and the peptide to which it binds. Although there are predictive algorithms that may be employed to predict peptides that can potentially bind to a particular MHC molecule, these algorithms yield false positive results, and the peptides must still be tested for binding to a particular MHC molecule.
Evidentiary reference Wieczorek et al. (Front. Immunol. 2017, volume 8, article 292: 1-16) teaches that the groove in between the a1 and a2 domains helices of MHC class I molecules accommodates peptides based on the formation of a set of conserved hydrogen bonds between the side chains of the MHC molecule and the backbone of the peptide and the occupation of defined pockets by peptide side chain anchor residues. Wieczorek et al. teach that the type of interactions of individual peptide side chains with the MHC depend upon the geometry, charge distribution and hydrophobicity of the peptide binding groove. Wieczorek et al. teach that prediction of peptide binding based upon bioinformatics algorithms (i.e., in silico predictions) yield false positive results.
Therefore, it appears that the instant specification does not adequately disclose the breadth of the isolated molecule comprising the antibody variable region recited in the instant claims. In light of this, a skilled artisan would reasonably conclude that Applicant was not in possession of the genus of all such isolated molecules at the time the instant application was filed.
6. 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.
7. Claims 1-4, 19, 20, 23-27 and 29 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 1 is indefinite in the recitation of “wherein the molecule does not specifically bind to the peptide in its wild-type form” because it is not clear what is meant, i.e., it is not clear whether it is meant that the molecule does not bind to a wild-type peptide (nominal antigen) alone or if it is meant that the molecule does not bind to a complex of an HLA molecule and the wild-type peptide (a cognate HLA/wild-type peptide complex whereas it does bind to a cognate HLA/mutant peptide derived from the wild-type (nonmutant, nonvariant, peptide). Claims 2-4, 19, 10, 23-27 and 29 are included in this rejection because they depend upon claim 1.
As the specification discloses at [0052] that mutant G12 peptides comprise G12 variants of the wild type peptide as well as overlapping sequences (see for example SEQ ID NO: 7 and 8), the said limitation encompasses any HLA binding peptide comprising a subsequence of a intracellular portion of an oncogenic KRAS protein comprising a G12 mutation.
8. For the purpose of prior art rejections, the filing date of the instant claim 3 is deemed to be the filing date of PCT/US2016/023673, i.e., 3/23/16, as the provisional applications do not support the claimed limitations of the instant application. Provisional application serial no. 62/136,843 does not provide support for SEQ ID NOs: 21-24, 37 or 38 and provisional application serial no. 62/186,455 does not provide support for SEQ ID NOs: 37 and 38.
For the purpose of prior art rejections, the filing date of the instant claim 29 is deemed to be the filing date of provisional application 62/186,455, i.e., 6/30/15, as provisional application serial no. 62/136,843 does not support the claimed limitations of the instant application. Provisional application serial no. 62/136,843 does not provide support for the isolated molecule further comprising an scFv which specifically binds to CD3.
For the purpose of prior art rejections, the filing date of the instant claims 1, 2, 4, 19, 20 and 23-27 is the filing date of provisional application serial no. 62/136,843, i.e., 3/23/15.
9. 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.
10. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
11. Independent claim 1 recites:
“An isolated molecule comprising an antibody variable region which specifically binds to a complex of a human leukocyte antigen (HLA) molecule and a peptide which is a portion of a protein, wherein the peptide comprises a mutant residue, and wherein the mutant residue is in an
intracellular epitope of the protein, wherein the molecule does not specifically bind to the HLA molecule when the HLA molecule is not in said complex, wherein the molecule does not specifically bind to the peptide in its wild-type form, and wherein the protein is an oncogenic KRAS protein comprising a G12 mutation.”
12. Claims 1, 2, 4, 19, 20, 23, 24, 26 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Vogelstein et al. (Science, 2013, 339: 1546-1558, IDS reference) in view of Warren and Holt (Human Immunol. 2010, 71: 245-254, IDS reference), Abrams et al. (Cell. Immunol. 1997, 182: 137-151), Miller et al. (PLOS ONE, 2012, 7(8):1-14, IDS reference), WO 03/070752 A2 (IDS reference), and Denkberg et al. (J. Immunol. 2002, 169: 4399-4407, IDS reference).
Claim interpretation: The specification discloses that the wild type KRAS peptide corresponds to the sequence of SEQ ID NO: 3 (KLVVVGAGGV) ([52]). As the specification discloses at [0052] that mutant G12 peptides comprise G12 variants of the wild type peptide as well as overlapping sequences (see for example SEQ ID NO: 7 and 8), the said limitation encompasses any HLA binding peptide comprising a subsequence of a intracellular portion of an oncogenic KRAS protein comprising a G12 mutation. The limitation “wherein the molecules does not specifically bind to the peptide in its wild-type form” recited in instant base claim 1 is being interpreted as either nominal peptide or peptide bound to the same HLA as is the mutant peptide (see indefiniteness rejection above in this office action).
Vogelstein et al. teach that cancer genomes can be exploited for the development of immunotherapies, that typical solid tumors contain mutations that alter the amino acid sequences of the proteins encoded by the affected genes, each of these alterations being foreign to the immune system. Vogelstein et al. teach that most proteins affected by mutations are intracellular, so they will not be visible to the immune system unless the mutant residue is presented in the context of an HLA protein. Vogelstein et al. teach that antibodies or T cells with reactivity to mutant peptides from these protein antigens can be administered as therapeutics. Vogelstein et al teach that in order to produce these therapeutics, one must determine that these proteins are expressed, but also that they can be processed and presented in the context of an HLA complex. Vogelstein et al teach using in silico analyses [for prediction of] binding affinities [of peptide subsequences from mutant proteins to HLA] it was estimated that a typical breast or colorectal cancer contains 7 to 10 mutant proteins [containing mutant subsequences thereof] that can bind to an individual patent’s HLA type. Vogelstein et al teach the identity of some of these proteins, including KRAS having a G12D mutation. Vogelstein et al teach that the mutated peptide can be presented [in complex with an HLA molecule] on the surface of an antigen presenting dendritic cell (see entire reference, especially “Genome-Based Medicines” section on page 1557 and last full sentence at column 3 on page 1553).
Vogelstein et al. do not teach a TCR-mimic (TCR-like) antibody that binds to a complex of HLA-A2/KRAS G12D peptide.
Warren and Holt teach that the KRAS G12D peptide (the same peptide taught by Vogelstein et al.) has the sequence KLVVVGADGV and has binding affinity for HLA-A*0201 (i.e., HLA-A2). Warren and Holt also teach the KRAS G12V peptide having the sequence KLVVVGAVGV that has binding affinity for HLA-A*0201. This said peptide is identical to instantly recited SEQ ID NO: 4. Warren and Holt further teach that “even single amino acid changes such as the hot spot mutations incurred by common tumor genes can be sufficient for CTLs to single out and selectively kill cells presenting the mutant peptide (see entire reference, especially Table 1 at the “G12D” mutation section on page 239, page 246 at the second full paragraph, first full paragraph at column 2 on page 138).
Abrams et al. teach that the ras p21 proto-oncogenes (Kras, H-ras, and N-ras) have been identified, described, and associated with a high frequency and spectrum of human cancers. Abrams et al. teach that in human cancers that harbor ras point mutations, it is the K-ras gene at codon 12 that is found frequently mutated, with replacement of the normal G residues to a D, V, or C residue (i.e., KLVVVGADGV, KLVVVGAVGV, or, KLVVVGACGV, respectively) wherein the sequence of the wild-type peptide is KLVVVGAGGV (amino acid residues 5-17). Abrams et al. teach that these peptides are restricted by HLA-A2 and are CD8+ T cell epitopes (i.e., they bind to HLA-A2 and in complex are able to generate CD8+ peptide-specific T cell lines, in vivo generated T cells lyse the tumor cells expressing the endogenous codon 12 mutation in vitro) and implications for adoptive immunotherapy using these T cells (see entire reference, especially abstract, first paragraph of Introduction, Table 4, paragraph spanning pages 148-149, and last paragraph of Discussion).
Miller et al. teach a method for construction of a TCR-like mAb Fab display molecule, wherein the Fab comprises specificities that selectively and specifically bind with nM affinity to a complex of an HLA-A2/b2m/tumor peptide epitope, but not to a complex having a different peptide, including on cancer cell lines in vitro and in vivo. Miller et al. teach that these TCR-like antibodies are useful for visualizing antigens presented on tumor or diseased cells, for delivering therapeutics in tumor and T cell based diseases, for detecting or visualizing a particular peptide/HLA complex before and after treatment, for studying intracellular generation of, trafficking of, and stability of the peptide/HLA complex on APCs. Miller et al. teach that their method advantageously generates TCR antibodies to these HLA-A2/b2m/tumor peptide epitope complexes because the library members are not subjected to clonal selection against self-antigens and this feature is coupled with the power of display selection, the binding members can be quickly and efficiently isolated, do not require affinity maturation, have affinity about 1,000 times better than that of TCRs for peptide/HLA complexes, are approximately 100-fold improved over TCR-like mAbs produced by classical hybridoma technologies with regard to affinity of binding (see entire reference, especially abstract, last paragraph of introduction section, second paragraph of results, Figs 1 and 2 and legends, paragraph spanning columns 1-2 on page 10, last two paragraphs on page 11 in discussion section).
WO 03/070752 A2 teaches display libraries comprising Fab or scFv antigen-binding TCR-like mAbs fragments, wherein the TCR-like Fab or scFv bind specifically to an HLA class I complex (e.g., HLA-A2 heavy chain/b2m/tumor peptide). WO 03/070752 A2 teaches that selection steps can comprise competing non-target complexes that lack the particular peptide epitope or that have a mutated peptide epitope relative to the target epitope. WO 03/070752 A2 teaches that non-target molecules can be used as competing molecules such as an HLA molecule which is not bound to a peptide. WO 03/070752 A2 teaches that the Fab or scFv must not bind to other HLA/peptide complexes, the peptide alone, or to empty HLA/b2m complexes, the latter of which are unstable. WO 03/070752 A2 teaches that the TCR-like antibodies exhibit binding characteristics as well as the fine specificity of a TCR-like molecule. (see entire reference, especially page 2 at lines 11-30, paragraph spanning pages 2-3, page 3 at lines 24-30, page 4 at lines 1-7,page 6 at lines 21-26, page 21 at line 6-26, paragraph spanning pages 21-22, page 22 at lines 14-16, page 47 at lines 16-29, page 48-page 50 at line 13, page 52 at lines 8-14, page 56 at lines 14-21, page 98 at lines 4-7, claims 35, 37-39, 41 and 42).
Denkberg et al. teach that some T cells (i.e., TCRs on T cells) and some TCR-mimic antibodies can recognize a mutant peptide version of a wild-type peptide, but not the native peptide (see entire reference, especially last two paragraphs in section spanning columns 1-2 on page 440 and discussion section).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have followed the directive of Vogelstein et al. in producing an antibody therapeutic as well as diagnostic reagents against HLA mutated peptide complexes, the mutant peptides being the KRAS G12 V, C, or D peptides taught by Warren and Holt and Abrams et al. that bind to HLA-A2, the antibodies being TCR-like fab or scFv antibodies such as taught by Miller et al., WO 03/070752 A2, and/or Denkberg et al. using display library technologies taught by the art references, including steps to ensure that the TCR-like antibodies recognize only the mutant peptide/HLA complex but not the HLA in complex with the wild type peptide or to the wild-type peptide or to an empty HLA complex without the peptide.
One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so, in order to create TCR-like antibodies that can be used to target intracellular peptide KRAS C, V, or D mutations on tumors.
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have attached a detectable label or a therapeutic agent to the TCR-like Fab or scFv.
One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so, because Miller et al. teach that these TCR-like antibodies are useful for visualizing antigens presented on tumor or diseased cells, for delivering therapeutics in tumor and T cell based diseases, for detecting or visualizing a particular peptide/HLA complex before and after treatment, for studying intracellular generation of, trafficking of, and stability of the peptide/HLA complex on APCs.
13. Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Vogelstein et al. (Science, 2013, 339: 1546-1558, IDS reference) in view of Warren and Holt (Human Immunol. 2010, 71: 245-254, IDS reference), Abrams et al. (Cell. Immunol. 1997, 182: 137-151), Miller et al. (PLOS ONE, 2012, 7(8):1-14, IDS reference), WO 03/070752 A2 (IDS reference), and Denkberg et al. (J. Immunol. 2002, 169: 4399-4407, IDS reference) as applied to claims 1, 2, 4, 19, 20, 23, 24, 26 and 27 above, and further in view of Baeuerle and Reinhardt (Cancer Res. 2009, 69(12): 2009).
The teachings and combination of Vogelstein et al. in view of Warren and Holt, Abrams et al., Miller et al., WO 03/070752 A2, and Denkberg et al. have been discussed above, hereafter referred to as the “combined references”.
The combined references do not teach that the isolated molecule that comprises the antibody variable region further comprises an scFv that specifically binds to CD3.
Baeuerle and Reinhardt teach that an approach to engage T cells for cancer therapy are antibodies which are bispecific for a surface target antigen on cancer cells and for CD3 on T cells. Baeuerle and Reinhardt teach that these bispecific antibodies may contribute to immunotherapy of cancer by redirecting the vast number of existing T cell clones in patients while ignoring many of the immune escape mechanisms that otherwise limit specific antitumor responses of T cell clones (See entire reference, especially abstract, Figure 1, last paragraph of reference.)
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have made a bispecific version of the TCR-like antibody taught by the combined references wherein the other specificity is anti-CD3 on T cells as taught by Baeuerle and Reinhardt.
One of ordinary skill in the art would have been motivated to do this to create a bispecific version of the antibody to bridge a tumor cell with a T cell, and with a reasonable expectation of success in doing so, as the art teaches how to make both specificities and Baeuerle and Reinhardt teach that bispecific antibodies comprising an anti-tumor specificity and an anti-CD3 specificity may offer advantages to treating tumors.
14. Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Vogelstein et al. (Science, 2013, 339: 1546-1558, IDS reference) in view of Warren and Holt (Human Immunol. 2010, 71: 245-254, IDS reference), Abrams et al. (Cell. Immunol. 1997, 182: 137-151), Miller et al. (PLOS ONE, 2012, 7(8):1-14, IDS reference), WO 03/070752 A2 (IDS reference), and Denkberg et al. (J. Immunol. 2002, 169: 4399-4407, IDS reference) as applied to claims 1, 2, 4, 19, 20, 23, 24, 26 and 27 above, and further in view of Klemp Gjertsen et al. (J. Mol. Med., 2003, 81: 43-50).
The teachings and combination of Vogelstein et al. in view of Warren and Holt, Abrams et al., Miller et al., WO 03/070752 A2, and Denkberg et al. have been discussed above, hereafter referred to as the “combined references”.
The combined references do not teach that the isolated molecule that comprises the antibody variable region is specific for a KRAS G12 mutant peptide in complex with HLA-A3.
Klemp Gjertsen et al. teach that the KRas G12C mutant peptide binds to HLA-A*0302 (HLA-A3) and the complex thereof could induce CTLs that are capable of killing target cells expressing HLA-A*0302 and said mutant peptide. (See entire reference.)
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have made a TCR-like antibody according to the teachings of the combined references, but having a specificity against HLA-A*0302/KRas G12C mutant peptide.
One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so, in order to create TCR-like antibodies that can be used to target intracellular peptide KRAS C mutation on tumors in HLA-A*0302 positive patients.
15. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
16. Claims 1, 2, 19, 24, 25 and 29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 11-15, 21-26 of copending Application No. 18/473,695. Although the claims at issue are not identical, they are not patentably distinct from each other because the molecule comprising a antigen-binding domain that can bind to an HLA/b2m complex recognizes a KRAS G12V mutant peptide recited in the claims of ‘695 are species of the instant claims and as such anticipate the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim interpretation: The specification discloses that the wild type KRAS peptide corresponds to the sequence of SEQ ID NO: 3 (KLVVVGAGGV) ([52]). As the specification discloses at [0052] that mutant G12 peptides comprise G12 variants of the wild type peptide as well as overlapping sequences (see for example SEQ ID NO: 7 and 8), the said limitation encompasses any HLA binding peptide comprising a subsequence of a intracellular portion of an oncogenic KRAS protein comprising a G12 mutation. The limitation “wherein the molecules does not specifically bind to the peptide in its wild-type form” recited in instant base claim 1 is being interpreted as either nominal peptide or peptide bound to the same HLA as is the mutant peptide (see indefiniteness rejection above in this office action).
Note that the antigen binding domains recited in base claim 1 of ‘695 bind to one of the KRAS G12 mutant peptides LVVVGAVGV, VVVGACGVGK, VVVGADGVGK, VVVGAVGVGK or VVGADGVGK (e.g., as is evidenced by pages 22-24 of the specification of ‘695). Also note that the HLA may be HLA-A2 or HLA-A3, the molecule may be an antibody fragment, including a scFv, or may be a bispecific T cell engager having an anti-CD3 specificity. Note that the antigen binding domain does not bind to a complex that includes a wild type version of the modified peptide. Although base claim 1 of ‘695 recites that the peptide is VVVGAVGVGK (SEQ ID NO: 22 of ‘695), the evidentiary disclosure cited above indicates that subsets of these cognate sequences bind to other peptides as well as is also noted above.
Claims 1, 2, 19, 24, 25 and 29 are directed to an invention not patentably distinct from claims 1, 11-15, 21-26 of commonly assigned 18/476,695 as enunciated supra.
The U.S. Patent and Trademark Office may not institute a derivation proceeding in the absence of a timely filed petition. The USPTO normally will not institute a derivation proceeding between applications or a patent and an application having common ownership (see 37 CFR 42.411). Commonly assigned 18/476,695, discussed above, may form the basis for a rejection of the noted claims under 35 U.S.C. 102 or 103 if the commonly assigned case qualifies as prior art under 35 U.S.C. 102(a)(2) and the patentably indistinct inventions were not commonly owned or deemed to be commonly owned not later than the effective filing date under 35 U.S.C. 100(i) of the claimed invention.
In order for the examiner to resolve this issue the applicant or patent owner can provide a statement under 35 U.S.C. 102(b)(2)(C) and 37 CFR 1.104(c)(4)(i) to the effect that the subject matter and the claimed invention, not later than the effective filing date of the claimed invention, were owned by the same person or subject to an obligation of assignment to the same person. Alternatively, the applicant or patent owner can provide a statement under 35 U.S.C. 102(c) and 37 CFR 1.104(c)(4)(ii) to the effect that the subject matter was developed and the claimed invention was made by or on behalf of one or more parties to a joint research agreement that was in effect on or before the effective filing date of the claimed invention, and the claimed invention was made as a result of activities undertaken within the scope of the joint research agreement; the application must also be amended to disclose the names of the parties to the joint research agreement.
A showing that the inventions were commonly owned or deemed to be commonly owned not later than the effective filing date under 35 U.S.C. 100(i) of the claimed invention will preclude a rejection under 35 U.S.C. 102 or 103 based upon the commonly assigned case. Alternatively, applicant may take action to amend or cancel claims such that the applications, or the patent and the application, no longer contain claims directed to patentably indistinct inventions.
17. Claims 1, 23, 26 and 27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 11-15, 21-26 of copending Application No. 18/473,695 in view of Miller et al. (PLOS ONE, 2012, 7(8):1-14, IDS reference)(as applied to claims 1, 2, 19, 24, 25 and 29 above).
The claims of 18/473,695 have been described above. The claims of ‘695 do not recite that the molecule further comprises a detectable label or a therapeutic agent.
Miller et al. teach a method for construction of a TCR-like mAb Fab display molecule, wherein the Fab comprises specificities that selectively and specifically bind with nM affinity to a complex of an HLA-A2/b2m/tumor peptide epitope, but not to a complex having a different peptide, including on cancer cell lines in vitro and in vivo. Miller et al. teach that these TCR-like antibodies are useful for visualizing antigens presented on tumor or diseased cells, for delivering therapeutics in tumor and T cell based diseases, for detecting or visualizing a particular peptide/HLA complex before and after treatment, for studying intracellular generation of, trafficking of, and stability of the peptide/HLA complex on APCs. Miller et al. teach that their method advantageously generates TCR antibodies to these HLA-A2/b2m/tumor peptide epitope complexes because the library members are not subjected to clonal selection against self-antigens and this feature is coupled with the power of display selection, the binding members can be quickly and efficiently isolated, do not require affinity maturation, have affinity about 1,000 times better than that of TCRs for peptide/HLA complexes, are approximately 100-fold improved over TCR-like mAbs produced by classical hybridoma technologies with regard to affinity of binding (see entire reference, especially abstract, last paragraph of introduction section, second paragraph of results, Figs 1 and 2 and legends, paragraph spanning columns 1-2 on page 10, last two paragraphs on page 11 in discussion section).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have comprised a label or a therapeutic agent on to the molecule recited in the claims of ‘695. It would also have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have determined that the antigen binding region does not bind nominal mutant peptide (i.e., peptide not in complex with an HLA molecule).
One of ordinary skill in the art would have been motivated to do this in order to produce a targeted therapeutic agent or a labeled agent for delivery of a therapeutic agent to a tumor cell or to visualize tumor cells as is taught by Miller et al., and with a reasonable expectation of success in doing so.
Claims 1, 23, 26 and 27 are directed to an invention not patentably distinct from claims 1, 11-15, 21-26 of commonly assigned 18/476,695 as enunciated supra.
The U.S. Patent and Trademark Office may not institute a derivation proceeding in the absence of a timely filed petition. The USPTO normally will not institute a derivation proceeding between applications or a patent and an application having common ownership (see 37 CFR 42.411). Commonly assigned 18/476,695, discussed above, may form the basis for a rejection of the noted claims under 35 U.S.C. 102 or 103 if the commonly assigned case qualifies as prior art under 35 U.S.C. 102(a)(2) and the patentably indistinct inventions were not commonly owned or deemed to be commonly owned not later than the effective filing date under 35 U.S.C. 100(i) of the claimed invention.
In order for the examiner to resolve this issue the applicant or patent owner can provide a statement under 35 U.S.C. 102(b)(2)(C) and 37 CFR 1.104(c)(4)(i) to the effect that the subject matter and the claimed invention, not later than the effective filing date of the claimed invention, were owned by the same person or subject to an obligation of assignment to the same person. Alternatively, the applicant or patent owner can provide a statement under 35 U.S.C. 102(c) and 37 CFR 1.104(c)(4)(ii) to the effect that the subject matter was developed and the claimed invention was made by or on behalf of one or more parties to a joint research agreement that was in effect on or before the effective filing date of the claimed invention, and the claimed invention was made as a result of activities undertaken within the scope of the joint research agreement; the application must also be amended to disclose the names of the parties to the joint research agreement.
A showing that the inventions were commonly owned or deemed to be commonly owned not later than the effective filing date under 35 U.S.C. 100(i) of the claimed invention will preclude a rejection under 35 U.S.C. 102 or 103 based upon the commonly assigned case. Alternatively, applicant may take action to amend or cancel claims such that the applications, or the patent and the application, no longer contain claims directed to patentably indistinct inventions.
18. Claim 3 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
19. SEQ ID NO: 21-24, 37 and 38 are free of the prior art.
20. No claim is allowed.
21. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIANNE DIBRINO whose telephone number is (571)272-0842. The examiner can normally be reached on M, T, Th, F.
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/Marianne DiBrino/
Marianne DiBrino, Ph.D.
Patent Examiner
Group 1640
Technology Center 1600
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641