DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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 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.
Priority
The instant application, filed 02/10/2023, is a 371 filing of PCT/US21/45698 filed 08/12/2021, and claims domestic benefit to US Provisional application 63/065,324, filed 08/13/2020.
Status of Claims/Application
Applicant’s preliminary amendment of 07/26/2023 is acknowledged. Claims 4-7, 14, 21, 26-27, 36, 41, and 50 are amended and claims 2-3, 8-13, 15-20, 22-23, 25, 28-31, 37-38, 42-49, and 51-56 are cancelled. Claims 1, 4-7, 14, 21, 24, 26-27, 32-36, 39-41, and 50 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/13/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
It is noted that the author’s name “Huston” was misspelled as “Houston” in the citation of NPL reference 16. The IDS has been annotated with the corrected spelling and the reference has been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
The application has the following sequence compliance deficiencies:
Claim 33 recites the sequence “SASYRKR” in the second to last line and does not identify the sequence with an appropriate SEQ ID NO. It is noted that, based on the sequence listing, the sequence is SEQ ID NO: 62.
The instant specification recites the following sequences without appropriate SEQ ID NOs:
Pages 17-18, [0071], recites “amino acids 691-699 of SEQ ID NO:1 (IMIGVLVGV), amino acids 605-613 of SEQ ID NO: 1 (YLSGANLNL), and amino acids 694-702 of SEQ ID NO:1 (GVLVGVALI)”; page 18, lines 2-3 recite “amino acids 691-699 of SEQ ID NO: 1 (IMIGVLVGV)” again. While the sequences recited in the parentheticals are comprised in SEQ ID NO: 1, the sequences are recited without the rest of SEQ ID NO: 1 and are each four amino acids or longer. As such, the sequences are required to have an accompanying SEQ ID NO.
Page 21, [0088], recites the sequence “IMIGVLVGV in both line 2 and in the Table 1 header without an accompanying SEQ ID NO.
Page 22, [0091], recites the sequence “IMIGVLVGV” in the Table 2 header without an accompanying SEQ ID NO.
Page 34, line 1 recites the sequence “SASYRKR” without an accompanying SEQ ID NO.
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," 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 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) 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") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) 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 of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
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.
Drawing Objections
The drawings are objected to for containing low quality images that are difficult to read. For instance, see Figs. 1, 4, and 5.
Additionally, Fig. 2 has three lines on the top right of the figure and it is unclear if this is part of the plot shown or an extraneous marking.
Claim Interpretation
Claims 1 and 39 recite the limitations “a cancer cell-specific antigen, or a peptide antigen thereof in complex with a major histocompatibility complex class I (MHC-I)” (part a.i.), “CEA cell adhesion molecule 5 (CEA), or a peptide antigen thereof in complex with a major histocompatibility complex class I (MHC-I)” (part a.ii.), and “BEST2, BEST4, SCARA5, EPHA7, and TGFBR2, or an antigen peptide thereof in complex with a major histocompatibility complex class I (MHC-I)” (part b.).
In the instant office action, the limitations concerning antigens being in complex with MHC-I are interpreted as applying to the peptide antigens only, interpreted as fragments, not the whole cancer antigen peptides (a cancer cell-specific antigen, CEA, BEST2, BEST4, SCARA5, EPHA7, and TGFBR2). This interpretation is supported by the use of “or” in the claims and the state of the art which acknowledges that fragments of peptides are presented in complex with MHC, not whole antigens.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 4-7, 14, 21, 24, 26-27, 32-36, 39-41, and 50 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.
Claims 1 and 39 recite the limitations “optionally a chimeric antigen receptor (CAR) or T cell receptor (TCR)” in part a. and “optionally an inhibitory chimeric antigen receptor (iCAR)” in part b. The use of “optionally” in these instances renders the claims indefinite as it is unclear if the limitations following the recitation, which are narrower embodiments of the preceding limitations, are a limiting feature of the claimed invention or an exemplary embodiment.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 1 and 39 recite the broad recitations “a first receptor” and “a second receptor”, and the claims also recite a CAR or TCR or an iCAR which are the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Appropriate correction is required.
Claims 4-7, 14, 21, 24, 26-27, 32-36, 40-41, and 50 are rejected by virtue of their dependency on rejected claim 1 as they do not resolve the ambiguity discussed above.
Claim 24 recites the limitation “the MHC-1”. Claim 1 recites multiple instances of MHC-I, once in part a and again in part b, rendering the limitation of claim 24 indefinite as it is unclear which MHC-I is being further limited. See MPEP 2173.05(e) which states “ if two different levers are recited earlier in the claim, the recitation of "said lever" in the same or subsequent claim would be unclear where it is uncertain which of the two levers was intended.“
Appropriate correction is required.
Claim 40 recites the limitation “the one or more polynucleotides of claim 39”. Claim 39 is not drawn to one or more polynucleotides, but rather is drawn to a polynucleotide system, comprising one or more polynucleotides. It is unclear if claim 40 includes the entire polynucleotide system of claim 39 or only the one or more polynucleotides comprised within the system rendering the metes and bounds of the claim indefinite.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)- Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 4-7, 14, 21, 24, 26-27, 32-36, 39-41, and 50 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.
Claims 1 and 39 encompass a first receptor, optionally a CAR or TCR, comprising an extracellular binding domain specific to a target antigen selected from a peptide antigen of a cancer specific antigen in complex with a MHC-I or a peptide antigen of CEA in complex with MHC-I; and a second receptor, optionally an iCAR, with an extracellular ligand binding domain that binds an antigen peptide of one of the target antigens recited in complex with a MHC-I. As such, claims 1 and 39 encompass a genus of binding domains that are claimed by what they do, specifically binding to an antigen fragment in complex with MHC-I, rather than what they are, specifically the structure that performs such function.
The instant disclosure, however, does not describe a representative number of species of the claimed genus of antigen binding domains that bind to an antigen fragment in complex with MHC-I. The disclosure also does not provide a structure function relationship that would allow an ordinarily skilled artisan to identify which antigen binding fragments would be capable of performing the claimed function.
The examples of the instant disclosure detail the identification of transmembrane proteins as potential candidate blockers for use as non-target antigens (Examples 1-2). The examples do not disclose a representative number of species of the claimed antigen binding domains or a structure-function relationship sufficient to demonstrate possession of the entire scope of the claimed genus.
The state of the art around the effective filing date of the claimed invention also does not provide a representative number of species or a predictable structure-function relationship to support the full scope of the claimed genus.
Neefjes, J. and H. Ovaa (2013) A peptide’s perspective on antigen presentation to the immune system Nature Chemical Biology (9); 796-775 provides a review of the immune response from the peptide’s perspective and discusses the fate of peptides in cells before presentation by MHC complexes. Neefjes discusses how peptides are altered post-translationally to yield immune responses (abstract). Neefjes teaches that T cells have antibody-like receptors (TCR) that recognize a noncovalent complex of peptides bound to an MHC molecule (page 769, left column, paragraph 3). MHC molecules are glycoproteins that stably bind peptides of defined length through noncovalent interactions. Although MHC class I is expressed on all of our cells, an analogous system, MHC class II, is expressed more selectively on immune cells (page 769, left column, paragraph 4). MHC class I and II complexes sample and present peptides that, in combination, are considered by the immune system (page 769, right column, paragraph 2). MHC class I complexes are more restrictive when it comes to peptide loading. The ends of the MHC class I peptide-binding groove interact with the free N and C termini of peptides, thus limiting binding to (mostly) peptides of nine amino acids in length (Fig. 2a,b). Longer peptides do not fit between the ends of the MHC class I peptide-binding grove, although some MHC complexes with longer peptides are known, in which the peptide cargo bulges out of the peptide-binding grove in the middle. MHC class II complexes do not command a strict peptide length as N and C termini can extend from both ends of the peptide groove (Fig 2b); usually, the size is limited to ~12 amino acids owning to protease processing of the peptide’s ends protruding out of the MHC class II peptide-binding grove (page 770, right column, paragraph 3).
Figure 1 in Neefjes provides a basic overview of peptide presentation by MHC molecules. As shown in the figure, proteins are degraded by protease into fragments which are then presented by the MHC molecules on the cells surfaces (page 771).
Neefjes teaches that the peptide recognized as non-self is an epitope that stimulates T cell response (page 771, right column; page 773, Fig. 3).
The teachings of Neefjes demonstrate that antigen presenting cells present peptide fragments, usually between only 9-12 amino acids in length forming a peptide epitope that is presented to T cells to stimulate responses. While the mechanism of peptide presentation by antigen presenting cells is discussed in detail in the prior art, the prior art demonstrates unpredictability in being able to identify and dictate what epitope of a peptide an antigen binding domain, such as an antibody or a binding fragment thereof, or a TCR, will interact with.
Hummer, A.M., et al (2022) Advances in computational structure-based antibody design Current Opinion in Structural Biology 74(102379); 1-7, which was published almost 2 years after the effective filing date of the claimed invention, demonstrates ongoing unpredictability between antibody binding and epitopes. Specifically, Hummer teaches that traditional methods for antibody development, such as deriving antibodies from hybridomas of inoculated animals or from library assembly followed by display techniques are not only costly and time consuming but also are not necessarily able to produce antibodies that bind to the desired site (epitope) on an antigen. Hummer teaches that computational antibody design methods offer a way to overcome these limitations, but are held back by the lack of accurate antibody and antigen structures (page 1, right column, paragraph 2). Hummer provides a review on how advances in protein structure prediction and other areas are bringing us closer to being able to entirely computationally designed antibodies that bind strongly to a defined epitope (page 1, right column, paragraph 3) demonstrating that in 2022 predictable structure function relationships were still not known. Hummer acknowledges this in their discussion of future directions stating that “Several challenges still remain for true computational structure-based antibody design. While there has been great progress in protein structure prediction, current methods are not yet able to accurately predict the position of the side chain atoms or structural changes on binding. For antibodies, accurately modeling the CDR-H3 loop remains a major obstacle. Additionally, improvements in paratope and epitope prediction, both in terms of accuracy and specificity (predicting the types of binding interactions for residues), will be needed to help improve docking for high-throughput virtual screening.” (page 4, right column, paragraph 3).
Hummer teaches the difficulties in predicting the relationship between antibody structure and the epitopes to which they bind demonstrating a lack of predictability in the field between antibody structure, such as those used in the antigen binding domains of CARs, and function.
Similar unpredictability is observed in the field of TCR binding domains.
Jokinen, E., et al (2021) Predicting recognition between T cell receptors and epitopes within TCRGP PLOS Computational Biology 17(3); e1008814; 1-27 teaches that to initiate an adequate adaptive immune response, a peptide, called an epitope, must first be bound by the major histocompatibility complex (MHC) class I or II molecule expressed on the surface of a nucleated cell or a professional antigen-presenting cell, respectively. The peptide-MHC complex is then presented to T cells which can recognize the complex via the TCR proteins, consequently leading to T cell activation and proliferation (page 2, paragraph 1). The CDRs of a TCR determine whether the TCR recognizes and binds to an antigen or not. Of these, CDR3 is the most variable and primarily interacts with the peptide, while CDR1 and CDR2 primarily interact with the peptide binding groove of the MHC protein presenting the peptide, but they can also be directly in contact with the peptide (page 2, paragraph 3). Jokinen teaches that we can characterize which TCRs recognize certain epitopes experimentally, but this is a time consuming task and is often not possible with scarce patient samples such as biopsies. However, previously produced experimental data has enabled the development of a computational method, TCRGP, that can predict which epitopes a TCR recognizes with higher accuracy than previous methods (abstract). Jokinen; however, teaches that even this model requires a sufficient amount of experimentally produced epitope-specific TCR-sequencing data be available to train a classifier. The exact number of TCRs required to achieve a certain level of accuracy also varies greatly between different epitopes. This likely reflects the fact that different epitopes can be more selective in choosing their TCR interactions. In other words, TCRs that recognize one epitope can be more diverse than the TCRs that recognize another epitope, and, if the TCRs are very heterogenous, it requires more sampling to get a representative sample of these TCRs for the model training. Jokinen teaches that, although computational methods cannot replace experimental measurements, they may be used to complement them when analyzing existing unselected TCR repertoire data or to guide experimental designs for ex vivo measurements (page 15, paragraph 3). With the currently available epitope-specific TCR sequence data we have come this far, but as more data becomes available with modern high-throughput techniques presented recently, new possibilities will rise. With a larger variety of pMHC complexes and TCRs that recognize them, we hope to better consider the cross-reactivity of TCRs, similarities between epitopes, and the significance of the HLA-types of the MHC proteins presenting the epitopes, and perhaps even predict if a TCR can recognize a previously unseen epitope (page 15, paragraph 4).
As discussed in detail above, Neefjes demonstrates that peptides are broken down into fragments for presentation, which form epitopes that are then presented in the context of MHC. Hummer and Jokinen demonstrate the unpredictable nature between antibody (CAR)/TCR binding domain structure and function when it comes to binding epitopes. These teachings demonstrate unpredictability in the identification of which antigen binding fragments are able to bind a peptide antigen that is in complex with an MHC as claimed.
It is not evident from the disclosure, or the prior art, that applicant was in possession of a representative number of species of the claimed genus, in which receptors, including CARs/TCRs, are claimed based on their function of binding to antigen peptides in complex with MHC-I. There is also no disclosed or art recognized structure-function correlation that would allow for the predictable identification of which receptor antigen binding domains, including CARs or TCRs, would be capable of performing such function. Therefore, the instant claims were determined to not meet the written description requirements of 35 USC 112(a).
Claims 32 and 34 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.
Claim 32 recites that the scFv comprises CDRs selected from SEQ ID NOs: 55-63, which encompasses a genus of scFvs comprising different combinations of the recited CDRs in any order.
Claim 34 recites that the scFv comprises a sequence having at least 85%, at least 90%, at least 95%, at least 97% or at least 99% identity to SEQ ID NOs: 64-67. As recited, the claim is drawn to a genus of scFvs with up to 15% modification (85% identity) anywhere in the recited sequences.
Both claims 32 and 34 depend on claim 27 and ultimately on claim 1, which requires that the claimed sequences be capable of binding to a target antigen.
The instant disclosure, however, does not describe a representative number of scFvs within the claimed genus while maintaining the claimed function. The disclosure also does not identify a structure-function relationship that could be used to predictably identify which of the claimed amino acid sequences could be used or modified in what way in order to arrive at antigen binding domains with the claimed functions. This is particularly the case as the claims do not require a full complement of 6 CDRs, specifically 3 from the heavy chain variable region/TCR β variable domain and 3 from the light chain variable region/ TCR α domain, which are the art recognized binding region of CARs and TCRs.
The examples of the instant disclosure details the identification of transmembrane proteins as potential candidate blockers for use as the non-target antigens (Examples 1-2). The examples do not disclose a representative number of species of the claimed antigen binding domains or a structure-function relationship sufficient to demonstrate possession of the entire scope of the claimed genus. The scFvs of SEQ ID NO: 64-70, comprising the full complement of 6 CDRs with 100% identity in combination, represents the species of the claimed genus that applicant was in possession of at the effective filing date of the claimed invention.
The state of the art around the effective filing date of the claimed invention also does not provide a representative number of species or a predictable structure-function relationship to support the full scope of the claimed genus.
For instance, Chiu, M.L., et al (2019) Antibody structure and function: The basis for engineering therapeutics Antibodies 8(55); 1-80 teaches that, the antigen-binding site of immunoglobulins is formed by the pairing of the variable domains (VH and VL) of the Fab region. Chiu teaches that each domain contributes three complementarity determining regions (CDRs), specifically, three from the VL and three from the VH, and that the six CDR loops are in proximity to each other resulting from the orientation of the VL and VH regions. Chiu teaches that the configuration of the VL and VH brings the three CDRs of the VL and VH domains together to form the antigen-binding site (page 4, paragraph 2). These teachings of Chiu demonstrate that the interaction between the heavy and light chain variable domains effect the conformation of the binding region of the antibody and therefore the antibody’s ability to bind to its target. Furthermore, the teachings of Chiu point out that the binding site is formed by the combination of the heavy and light chain CDRs (six regions) together. Based on these teachings, an ordinarily skilled artisan would not have been able to predictably identify which species of the instantly claimed genus would be capable of performing the claimed function. This is particularly the case in the absence of a full complement of heavy and light chain CDRs.
Rabia, L., et al (2018) Understanding and overcoming trade-offs between antibody affinity, specificity, stability, and solubility Biochem Eng. J. 15(137); 365-374 discusses similar challenges faced during antibody optimization. Rabia discusses the challenges with optimizing antibody properties and states that “natural antibody affinity maturation relies on the introduction of somatic mutations followed by clonal selection of antibody variants with improved affinity. However, not all somatic mutations contribute to antibody affinity… antibodies accumulate some somatic mutations to increase affinity and others to compensate for the destabilizing effects of affinity-enhancing mutations” (page 2, paragraph 4). Rabia further provides an example of researchers who introduced mutations throughout variable frameworks and CDRs and created libraries to sort antibody variants with high antigen binding. In this case an antibody was identified that displayed increased affinity but had a significant reduction in stability (page 3, paragraph 2). Rabia concludes by stating that “a final key area of future work is the development of improved computational methods for predicting mutations in antibody CDRs and frameworks that co-optimize multiple antibody properties” and that “future efforts will also need to improve structural predictions of antibody CDRs – especially the long and highly variable heavy chain CDR3 – to accurately predict CDR mutations that are beneficial to different antibody properties” (page 9, paragraph 4 – page 10 paragraph 2).
Based on the teachings of Rabia, introducing mutations in the antibody structure, particularly in the CDR regions, is not a predictable task and requires experimentation following mutation to ensure that the binding affinity is maintained and a specific, stable antibody is created. Rabia further spoke to the use of libraries and computational methods for predicting and co-optimizing antibody properties and teaches that these methods are not robust enough yet to yield predictable results. These teachings demonstrate that a modification to even one amino acid of an antibody, particularly in the CDRs, would likely result in an antibody that does not retain the specific binding functions as recited in the instant claims.
Rojas, G. (2022) Understanding and Modulating Antibody Fine Specificity: Lessons from Combinatorial Biology Antibodies 11(48); 1-22, which was published two years after the effective filing date of the claimed invention, demonstrates that antibody structure and function were still not predictable years after the effective filing date. For instance, Rojas teaches that epitope mapping results using mutagenesis scanning challenge our notions of conservative and nonconservative amino acid replacements. Several measures have been proposed to evaluate the difference between amino acids, based on physico-chemical distance between them, mutational distance, or evolutionary exchangeability. Tolerability profile to mutations within functional epitopes does not adjust strictly to any of these rules. The critical attributes of each amino acid that should be kept to maintain recognition depend on the particular antibody. For instance, sometimes only tyrosine and phenylalanine residues can be exchanged without effecting antigenicity, pointing to the relevance of their almost-identical aromatic rings, whereas in other epitopes, tyrosine and histidine are exchangeable, reflecting that two different rings can fulfill a similar functional role (page 11, paragraph 1). Teachings which demonstrate that even years after the effective filing date of the claimed invention even modifications using conservative substitution were not predictable.
It is not evident from the disclosure, or the prior art, that applicant was in possession of a representative number of species supporting the entire genus of scFvs that are encompassed by the instant the claims. Additionally, there is no disclosed or art recognized structure-function relationship between antibody structure and functionality which would allow for the predictable modification of the claimed sequences while maintaining a specific binding function. Therefore, instant claims 32 and 34 are found to not meet the written description requirement.
It is noted that there would be support for variation in the scFv of claim 34 if the full complement of 6 CDRs were limited to 100% identity.
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4-7, 14, 21, 24, 26-27, 36, 39-41, and 50 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2015/142314 A1 (Fedorov, V.D. and M. Sadelain) 24 SEPT 2015 in view of Herath, N.I., et al (2012) Complex expression patterns of Eph receptor tyrosine kinases and their ephrin ligands in colorectal carcinogenesis European Journal of Cancer 48; 753-762 and Parkhurst, M.R., et al (2009) Characterization of Genetically modified T cell receptors that recognize the CEA:691-699 peptide in the context of HLA-A2.1 on human colorectal cancer cells Clin Cancer Res 15(1); 169-180.
WO’314 teaches immunoresponsive cells including an antigen recognizing receptor that binds a first antigen and an inhibitory chimeric antigen receptor (iCAR) that binds a second antigen, wherein the binding of the antigen recognizing receptor to the first antigen activates the immunosuppressive cell, and the binding of the iCAR to the second antigen inhibits the immunosuppressive cell. WO’314 also teaches methods of producing the immunoresponsive cells, and methods of treating cancers using the cells (page 1, lines 9-15).
WO’314 teaches that T cell based therapies have curative potential in cancer immunotherapy; however, major treatment-related complications stem from unintended T cell reactivity against normal tissues, such as GVHD following donor lymphocyte infusion or “on-target, off-tumor reactivity” in autologous targeted T-cell therapy (page 1, lines 18-23). In an effort to prevent the consequences of cellular side effects, WO’314 teaches immunoresponsive cells, e.g., T cells, NK cells, CTLs, and regulatory T cells, expressing an antigen binding receptor, e.g., CAR or TCR, having immune cell activating activity and an inhibitory chimeric antigen receptor (iCAR) that selectively reduces or eliminates the immune activity of the immunoresponsive cell. Thus, off-target effects of the immunoresponsive cell are reduced (page 2, lines 19-24).
Figure 1A of WO’314 provides a schematic of the immunoresponsive cells and demonstrates that T cells with specificity for both tumor and off-target tissues can be restricted to tumor only by using an antigen-specific iCAR introduced into the T cells to protect the off-target tissue (page 20, lines 15-18). Fig. 1A is duplicated below:
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WO’314 teaches that the first antigen, or the antigen of the antigen recognizing receptor, is a tumor antigen selected from a group that includes CEA (page 5, lines 1-14).
WO’314 teaches that the iCAR approach is antigen-specific and thus requires the ability to identify tissue-specific target antigens that are absent or down-regulated on the tumor but expressed by the off-target tissue (page 74, lines 8-10). WO’314 further teaches that antigen disparity between a target and off target tissue can be limited with differences primarily in the level of expression rather than the absolute absence of expression (page 33, lines 9-11). WO’314 teaches that an appropriate target for the iCARs will at times utilize a personalized medicine approach due to natural variation in tumors. At the same time, depending on the use and type of iCAR, several potential “classes” of antigens have the potential to provide protection for several tissues at the same time. These include universally expressed immunogenic antigens that are down regulated by tumors but not normal tissues and antigens down regulated in tumor progression, especially the attainment of metastatic phenotype, but maintained in certain tissues. Additionally, there are many other processes disrupted in tumors including metabolic, apoptosis, trafficking, differentiation and the like, that each lead to down regulation of surface antigens and any of these could be used as potential iCAR antigen targets (page 32, lines 1-23).
WO’314 further teaches a method of reducing tumor burden in a subject involving administering an effective amount of the immunoresponsive cell. The method can selectively target tumor cells compared to non-tumor cells. In some embodiments, the method recues the number of tumor cells, reduces tumor size, or eradicates the tumor in the subject (page 3, lines 1-4). WO’314 further teaches cancers that the cells can be used to treat cancers including colon carcinomas, AML, and pancreatic cancer (page 16, lines 4-24).
WO’314 further teaches pharmaceutical compositions for the treatment of a neoplasia including an effective amount of the immunoresponsive cell in a pharmaceutically acceptable excipient (page 4, lines 11-13).
WO’314 further teaches that the antigen recognizing receptor is a T cell receptor (TCR) or chimeric antigen receptor (CAR) and can be exogenous of endogenous. The antigen recognizing receptor can be recombinantly expressed by a vector (page 6, lines 4-10). The term “chimeric antigen receptor” or “CAR” refers to an antigen-binding domain that is fused to an intracellular signaling domain capable of activating or stimulating an immune cell. Most commonly, the CAR’s extracellular binding domain is composed of a single chain variable fragment (scFv) derived from fusing the variable heavy and light regions of a murine or humanized monoclonal antibody. Alternatively, scFvs may be used that are derived from Fabs (page 8, lines 13-21).
WO’314 further teaches nucleic acids and vectors including the nucleic acids that encode the iCAR (page 4, lines 4-10).
WO’314 teaches that genetic modification of immunoresponsive cells, e.g., T cells, CTL cells, NK cells, can be accomplished by transducing a substantially homogenous cell composition with a recombinant DNA or RNA construct. Preferably, a retroviral rector is employed for the induction of the DNA or RNA construct into the host cell genome. For example, a polynucleotide encoding a receptor that binds to an antigen can be cloned into a retroviral vector and expression can be driven from its endogenous promoter, from the retroviral long term repeat, or from an alternative internal promoter (page 42, lines 1-9). Possible methods of transduction include direct co-culture of the cells with producer cells or culturing with viral supernatant alone or concentrated vector stocks (page 42, lines 28-32).
WO’314 further provides a schematic representation of a selection of target antigen for iCAR and CAR (page 27, lines 20-21; Figure 23) in which a tumor biopsy/sample is selected, surface antigen profiling is performed and compared to repositories, absent or low level expressing surface antigens are identified and are viable iCAR antigens, the expression in normal or non-neoplastic tissue/cell expression is identified and becomes tissues that can be protected, then, depending on the positive/stimulating signal, a patient specific antigen and corresponding scFv or antigen recognition domain for the iCAR is identified.
The teachings of WO’314 differ from the instantly claimed invention in that WO’314 does not teach that the iCAR is specific to an antigen selected from BEST2, BEST4, SCARA5, EPHA7, and TGFBR2 or an antigen peptide thereof in complex with MHC-I. WO’314 also does not teach the pairing of one of these iCAR antigen targets with an antigen binding receptor targeting CEA specifically.
Herath teaches that aberrant expression of Eph and ephrin proteins in human cancers is extensively documented. Herath analyzed expression of all Eph and ephrin genes in colorectal cancer (CRC) cell lines and 153 clinical specimens, providing a comprehensive analysis of the system in CRC. Eph/ephrin mRNA expression was assessed by quantitative real-time PCR and correlated with protein expression using flow cytometry, western blotting, and immunocytochemistry. Herath teaches that EphA1, EphA2, EphB2 and EphB4 were significantly over expressed in CRC. In all cases at least one Eph gene was found in the normal colon, where expression was observed at high levels in most CRC. However, other Eph gene expression was lost in individual CRCs compared to the corresponding normal, EphA7 being a striking example. Loss of expression was more common in advanced disease and thus correlated with poor survival (abstract).
Herath teaches that EphA7 expression has in fact been shown to be lost in most CRC, apparently through epigenetic gene silencing (page 754, left column, paragraph 3). Herath provides a comparison between the average expression of EphA7 in normal colon and CRCs assessed through colon tissue Q-PCR arrays as well as a log fold relative comparison between EphA7 mRNA expression in pared normal and CRC specimens (page 758, Fig. 4A; page 760, Fig 5C). The EphA7 expression levels from Fig. 4A and 5C are shown below for convenience:
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Parkhurst teaches that carcinoembryonic antigen (CEA; CEACAM5; CD66e) is a 180-kDA glycoprotein often highly overexpressed in colorectal cancers and selected other epithelial cancers and is thus an attractive target for cell transfer immunotherapy (page 2, paragraph 2). CEA was originally described in 1965 by Gold and Freeman as an oncofetal antigen expressed during fetal development and in cancers of the human digestive system, but not in normal adult tissues. Since that time, CEA has been extensively investigated as a tumor-specific marker for the detection, diagnosis, prognosis, treatment monitoring, localization, and therapy of a variety of different cancers. Expression of CEA protein by tumor cells has been extensively studied using immunohistochemistry with many different polyclonal and monoclonal antibodies. Immunohistochemically, CEA has been found in cancers of the colorectum, breast, lung, cervix, gallbladder, stomach, pancreas, liver, prostate, urinary bladder, ovaries, uterus, and head and neck and in neuroendocrine tumors from the larynx, lung, and thyroid. CEA expression in normal adult tissues is considerably more limited, but is present in columnar epithelial cells and goblet cells in the colon, in mucus cells in the neck and stomach, in squamous epithelial cells of the tongue, esophagus, cervix, in secretory epithelial and duct cells of sweat glands, and in epithelial cells of the prostate (page 10, paragraph 1). CEA is clearly expressed on a variety of different cancers, but is also expressed in some normal adult tissues, most notably colonic epithelial cells in the upper third of colonic crypts. Thus, there is significant concern about potential toxicities that might be induced by the adoptive transfer of large numbers of CEA-reactive T cells (page 12, paragraph 2).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to substitute the iCAR target antigens in the immune cell of WO’314 with EphA7 based on the teachings of Herath, particularly paired with a CEA targeting CAR/TCR based on the teachings of Parkhurst. An ordinarily skilled artisan would have been motivated to use EphA7 as the target antigen for the iCAR as Herath demonstrates loss of EphA7 in colorectal cancer cells compared to corresponding normal cells. The selection of EphA7 as the iCAR antigen target in combination with a CAR/TCR targeting CEA is further supported by Parkhurst which teaches that CEA is expressed on a variety of cancers including colorectal cancers and pancreatic cancers and is also expressed to a limited degree on normal cells including cells in the colon. Additionally, Parkhurst teaches that the expression of CEA on normal cells raises concerns about toxicity during adoptive cell transfer, which acts to further motivate the inclusion of an iCAR when targeting CEA as WO’314 teaches that the inclusion of an iCAR in the cell can reduce toxicities including on-target off-tumor toxicities. An ordinarily skilled artisan would have had a reasonable expectation of success as WO’314 teaches that an appropriate target for the iCAR can include those that are down regulated by tumors but not normal tissues and those that are down regulated in tumor progression, but maintained in other tissues. Furthermore, WO’314 teaches that the use of an iCAR targeting down regulated antigens can reduce on-target off-tumor toxicities, such as those described by Parkhurst as being a concern for transfer of CEA reactive T cells.
Regarding claims 7 and 24, Parkhurst further teaches that to develop an immunotherapy for patients with cancers that overexpress CEA, TCRs were isolated and genetically modified to specifically bind a CEA peptide on human cancer cells (abstract, purpose). In particular, TCRs reactive with CEA were isolated by immunizing HLA-A2.1 transgenic mice with CEA-derived peptides containing amino acid sequences different from those present in any murine CEA-related protein. Additionally, amino acid substitutions in the CDRs of the α and β chains from the CEA reactive TCR were evaluated. The combination of these two strategies enabled the generation of high-affinity TCRs capable of conferring CEA reactivity to both CD4+ and CD8+ human T cells (page 2, paragraph 2). Parkhurst teaches that the identification of the modified TCRs provides significant flexibility for use in clinical trials of TCR gene-modified lymphocytes and that highly specific anti-CEA CD8+ T cells could be generated using the disclosed receptor (page 11, paragraph 3). The TCRs disclosed by Parkhurst recognize CEA:691-699 peptide in the context of HLA-A2.1 (title; abstract, experimental design).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to use the TCRs disclosed by Parkhurst as the antigen recognizing receptor in the immunoresponsive cells of WO’314. An ordinarily skilled artisan would have been motivated to use the TCRs which recognize a peptide antigen of CEA in complex with HLA-A2.1 as Parkhurst teaches that the TCRs specifically bind to CEA peptides on human cancer cells with improved recognition of CEA. Additionally, Parkhurst discloses that the TCRs disclosed enhanced tumor cell recognition by CD8+ and CD4+ T cells (abstract, results). An ordinarily skilled artisan would have had a reasonable expectation of success because WO’314 teaches that the antigen recognition receptor in the immunoresponsive cells can be a TCR, that the antigen can be CEA, and that the cells can be used in the treatment of cancers which Parkhurst recognizes as expressing CEA including colon and pancreatic cancers.
Regarding claim 14, as discussed in detail above, WO’314 teaches that the iCAR approach is antigen-specific and requires the ability to identify tissue-specific target antigens that are absent or down-regulated on the tumor but expressed by off-target tissues (page 74, lines 8-10). WO’314 also teaches methods to identify targets for the iCAR on a case-by-case basis using samples/biopsies from tumors (Figure 23). In the case that the iCAR target is absent in the tumor but expressed by off-target tissues, the absence of the antigen would meet the limitations of instant claim 14. Furthermore, Herath provides data concerning the expression of EphA7 and demonstrates an on average downregulation of approximately 7 times in patients with colorectal cancers versus controls with error bars that demonstrate that much higher differences were present (Fig. 4). Herath further demonstrates as much as a -3.5 log difference between CRC EphA7 expression and expression in normal cells (Fig. 5), which is well below a 110 times difference.
Furthermore, the determination of an optimal numerical difference between the iCAR antigen target expression on healthy cells versus the cancer cell is considered to be routine optimization as considerations for such determination were known in the art.
MPEP 2144.05 (II) A. states that "’[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.’ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)” and "It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention,