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 .
Priority
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in Europe on 15 July 2022. It is noted, however, that applicant has not filed a certified copy of the European application as required by 37 CFR 1.55. The effective filing date is 17 July 2023.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 15 November 2023 and 18 December 2023 are being considered by the examiner.
Status of Application, Amendments, and/or Claims
Claims 1-42 are the original claims filed on 17 July 2023. In the preliminary amendment of 16 November 2023, claims 2, 3, 5-8, 10, 12, 13, 16, 19, 21-25, 28, 29, 32, and 37-42, claims 1, 4, 9, 11, 14, 15, 17, 20, 26, 27, 30, 31, and 33-36 are amended, and claims 43-50 are new. Claims 1, 4, 9, 11, 14, 15, 17, 18, 20, 26, 27, 30, 31, 33-36, and 43-50 are pending and the subject of this office action.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 4, 11, 17, 18, 20, 27, 33, 34, 36, and 43-50 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.
Regarding claims 1, 4, 18, and 20, the applicant refers to either a soluble γ or δ T-cell receptor chain with a CDR3 comprising an amino sequence derived from SEQ ID NO:1 or SEQ ID NO:2, respectively. The claims establish that the CDR3s must share at least 60 % sequence identity or similarity with the reference sequences, from which they are derived, with the added requirement that one or more amino acids be modified within specified ranges of positions, relative to the reference sequence (claim 1 refers to either positions 4-10 or 5-9 of SEQ ID NO: 1 and claim 18 refers to positions 7-12 of SEQ ID NO: 2). A modification, as defined within the specification, refers to alterations of an amino acid sequence (or the nucleic acid encoding the corresponding amino acid sequence), in which an amino acid is substituted, inserted, deleted, or any combination thereof (page 6 lines 16-24). The combination of these extremely broad limitations, with no functional limitations, allow the scope of the claimed invention to encompass an inappropriate number of potential T-cell receptors. As an example, the following alignments of modified amino acid sequences derived from SEQ ID Nos: 1 and 2 and their corresponding reference sequences are provided, with % sequence identities calculated using an algorithm cited in the specification, EMBOSS Needle (page 87 lines 7-15):
SEQ ID NO: 1 CATWDGFYYKKLF 13 Sequence Identity 61.5%
CATW KKLF
Position 5-9 deleted CATW-----KKLF 8 Sequence Similarity 61.5%
SEQ ID NO: 2 CAASSPIRGYTGSDKLIF 18 Sequence Identity 66.7%
CAASSP SDKLIF
Positions 7-12 deleted CAASSP------SDKLIF 12 Sequence Similarity 66.7%
As shown in the alignment above, the scope of limitations established in claims 1 and 18 is broad enough to allow for the deletion of the entire range specified, which in turn introduces an additional level of indefiniteness when one begins to introduce limitations referring to specific positions within the range, such an in instant claims 4 and 20. When multiple modifications, specifically at least one insertion or deletion, are made, the relative position of an amino acid substitution becomes impossible to assign relative to the numbering referenced in claims 4 and 20. In the example below, one could not assign a position, relative to SEQ ID NO:2, for the lysine or the phenylalanine, which is relevant to claim 20 and the same logic could be applied to claim 4.
SEQ ID NO: 2 1 CAASSPIRGYTGSDKLIF 18 Sequence Identity 66.7%
|||||| . . ||||||
Example 1 CAASSP-K-F--SDKLIF 13 Sequence Similarity 66.7%
In regard to claim 49 and 50, claim 49 recites the limitation "an effective amount of a soluble T-cell receptor or fragment thereof as defined in claim 15" in lines 1 and 2. There is insufficient antecedent basis for this limitation in the claim, as the referenced claim, claim 15, only refers to a γ T-cell receptor chain or fragment thereof. Claim 49 is referring to a γδ T-cell receptor or fragment thereof. This discrepancy leaves the nature of the receptor or fragment thereof as being undefined. Claim 50 is dependent on claim 49 and as a result is also rejected.
In regard to claims 17 and 33, both claims refer to TCR chains, with the added functional limitation that they are capable of mediating anti-infective or anti-tumor responses. The claims also state that chains mediate these responses by acting against certain targets, as stated in the following excerpt: ”preferably against a target cell expressing endothelial protein C receptor (EPCR).” As written, it is unclear if the targeting of a cell expressing the endothelial protein C receptor is a required limitation of the claim, see MPEP 2173.05(h).
Claims 11, 27, 34, 36, and 43-48 are rejected under 35 USC 112(b) by virtue of their dependency on a rejected claim.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 4, 9, 11, 14, 15, 17, 18, 20, 26, 27, 30, 31, 33, 34 ,and 35 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is “undue” include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731,737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Regarding the nature of the invention, the invention describes soluble gamma and delta T cell receptor chains or fragments thereof and gamma delta T cell receptors or fragments thereof comprising CDR3 amino acid sequences derived from SEQ ID NOs: 1 and 2, respectively. However, claims 17 and 33 describe T cell receptors chains or fragments thereof, comprised of sequences sharing at least 60% identity to SEQ ID NOs: 1 or 2, as described in claims 1 and 17, capable of mediating anti-tumor or anti-infective responses, preferably against a target cell expressing endothelial protein C receptor (EPCR). Claims 17 and 33 have the functional limitation of anti-tumor or anti-infective response mediation, which is enabled for SEQ ID NOS: 10 and 23 when coupled with their corresponding delta or gamma chain (figures 13, 14, 15, table 2). However, the scope of the claims extends beyond the function defined by the CDR3 sequences of the working examples (SEQ ID 10 and 23), due to the allowed 40 % CDR3 sequence variation, as written in the claims. Additionally, as written, claims 1, 4, 11, 14, 15, 17, 18, 20, 26, 27, 30, 31, and 33 only refer to single TCR chains, and make no mention of their complementary counterparts.
It is also widely known in the art that the variable domains of T cell receptors and immunoglobulins share a similar β-sandwich architecture, and require six CDRs for antigen recognition. Chien YH, et al. (2014) γδ T cells: first line of defense and beyond. Annu Rev Immunol. 2014;32:121-55 (herein Chien) states that “the mode of γδ TCR recognition of antigen resembles Ig antigen recognition.” Chien also teaches that computational modeling shows that CDR length has a profound effect on the loops shape, and that CDR3 regions from γδ T cell receptors and Igs have closely aligned trends in CDR3 length and variability (Figure 2, Comparison of the CDR3 length distributions of all immune receptor chains: paragraph one). Thus, due to the structural and functional homology shared between variable domains of immunoglobulins and γδ T cell receptors, teachings regarding antibody variable domain design/engineering as well as associated antigen recognition are applicable to the design/engineering of T cell receptor antigen specificity.
Rabia L, et al. (2018) Understanding and overcoming tradeoffs between antibody affinity, specificity, stability, and solubility. Biochem Eng. J. 15(137); 365-374 discusses the challenges with optimizing antibody properties and states “the most important antibody properties relate to their natural functions, such as their high binding affinity and specificity mediated by their complementarity-determining regions (CDRs) within the variable regions... Other key natural antibody properties include their effector functions — such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC)- which are mediated by their constant regions” (page 2, paragraph 1). Rabia further teaches that “most antibodies identified during the initial discovery process are not suitable for therapeutic use and require additional optimization. For example, the binding affinities of some lead antibodies are not high enough for therapeutic applications” (page 2, paragraph 3). Rabia goes on to state 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).
Additionally, the prior art clearly demonstrates that T cell receptor and immunoglobulin functionality is dependent on the entire protein structure, particularly a full complement of six CDRs. Chiu ML, et al. (2019) Antibody Structure and Function: The Basis for Engineering Therapeutics. Antibodies (Basel). Dec 3;8(4):55 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). Here, Chiu teaches that the interaction between the heavy and light chain variable domains effects 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.
In regards to claims 1, 4, 11, 14, 15, 17, 18, 20, 26, 27, 30, 31, and 33, the claims describe either gamma or delta TCR chains. No structural definitions are assigned to the complementary chains. Based on the teachings of Chiu, which state that the functional characteristics of antigen binding domains are primarily defined by the 6 CDRs contributed by the two chains of the complex, an ordinarily skilled artisan would not have been able to predict the characteristics, both in terms of ligand specificity or overall stability, of a TCR, in which only a single chain (3 CDRS) is defined. With the exception of claims 17 and 33, no functional limitations are placed upon the TCR chains, and as discussed above, it would be impossible to predict the ligand specificity of a TCR, in which only half of the CDRs are defined. Table 2 of the specification does provide working examples of paired gamma and delta TCR chains, but the claims fail to link the complementary chains. Neither, the prior art nor the description has enabled the use of T cell receptors with unknown ligand specificity.
Additionally, claims 17 and 33, as written, introduce a requirement that the referenced TCR chains or fragments thereof must be capable of mediating an anti-infective or anti-tumor response. Neither the prior art nor the current disclosure has demonstrated that a single TCR chain is capable of mediating either of the referenced responses. In addition, as discussed above, neither the specification nor the prior art, has enabled the use of a T cell receptor, in which only the structure of one chain is defined, to mediate the responses referenced in the claims.
In addition to the lack of enablement associated with the undefined structure of TCR chain complementarity pairings, claims 1, 4, 9, 11, 17, 18, 20, 25, 27, 33, 34, and 35 also fail the enablement requirement due to the large degree of sequence variation allowed in their claim limitations.
As taught by Rabia, the prior art is quite clear that the modification of CDRs, specifically the CDR3, is not predictable and requires significant experimentation following mutation to ensure that binding affinity is maintained and a stable protein is created. Rabia further spoke to the use of libraries and computational methods for predicting and co-optimizing properties and demonstrated how these methods are not robust enough yet to yield predictable results. This teaching demonstrates that modifications to the sequences of the claimed invention could have unpredictable results and could result in functional or biochemical properties, which the current disclosure has not properly enabled.
Based on the teachings of Rabia, introducing mutations in CDRs, particularly in the CDR3 regions, is not predictable and requires experimentation following mutation to ensure that binding affinity is maintained and a stable protein is created. Rabia further spoke to the use of libraries and computational methods for predicting and co-optimizing antibody properties and demonstrated how these methods are not robust enough yet to yield predictable results. This teaching demonstrates that modifications to the sequences of the claimed invention could result in a γδ T cell receptor with unpredictable characteristics (i.e. ligand specificity), and could result in a receptor not suitable for mediating anti-tumor or anti-infective responses, which is relevant to claims 17 and 33.
Claims 1, 4, 11, 18, 20, 27, and 34 allow for up to 40% sequence variation in the CDR3 of their respective chains, which in the case of claims 11 and 27, is further compounded by the allowance of up to 30% variation in the CDR1 and CDR2 of their respective chains. Unlike claims 17 and 33, these chains lack of functional limitations. As taught by Rabia, the effects of CDR modifications are not predictable, and the allowance of such large degrees of variation, even when factoring in the minor positional limitations established in claims 4 and 20, would make predicting the functional characteristics of the resulting receptors, receptor chains, or fragments thereof impossible. As discussed above, neither the prior art nor the current disclosure enables the use of TCR receptors, TCR receptor chains, or fragments thereof with unknown ligand specificity. In regard to claims 9, 26, and 35, in which the allowed 40% sequence variation remains intact, the added limitation, that the CDR3s are comprised of one of a series of short amino acid sequences, would still allow for a degree of variation within the CDR3 regions that would make predictions regarding functional characteristics of the resulting receptor, receptor chain, or fragment thereof impossible.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 11 and 27 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 11 and 27 are drawn to either γ (claim 11) or δ (claim 27) T cell receptor chains or fragments thereof, wherein the CDR1 and CDR2 share at least 70 % sequence identity to reference sequences (γCDR1 comprises SEQ ID NO: 375, γCDR2 comprises SEQ ID NO: 376, δCDR1 comprises SEQ ID NO: 377, and δCDR2 comprises SEQ ID NO: 378). The claims are dependent on either claim 1 (γ TCR chain) or claim 18 (δ TCR chain), both of which define the corresponding CDR3 as having at least 60% sequence identity or similarity to SEQ ID NO: 1 or SEQ ID NO: 2, respectively. However, the T cell receptor chains disclosed in the instant application all contain consistent CDR1 and CDR2 sequences, with the only variation occurring within the CDR3 regions of both the delta and gamma chains (figure 1, page 102 lines 16-37).
The art demonstrates that T cell receptor and immunoglobulin functionality is dependent on the entire protein structure, particularly a full complement of six CDRs. As discussed previously, due to the structural and functional homology shared between variable domains of immunoglobulins and γδ T cell receptors, teachings regarding antibody variable domain design/engineering as well as associated antigen recognition are applicable to the design/engineering of T cell receptor antigen specificity. Chiu ML, et al. (2019) Antibody Structure and Function: The Basis for Engineering Therapeutics. Antibodies (Basel). Dec 3;8(4):55 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). Here, Chiu teaches that the interaction between the heavy and light chain variable domains effects 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 determine which amino acids in which CDR regions could be modified such that the antibody would be biochemically stable or retain similar functionality.
Neither the prior art nor the instant disclosure, however, provide adequate evidence nor does the disclosure provide a structure-function correlation that would allow for an ordinarily skilled artisan to envision what variation can occur in the delta or gamma chains, particularly in the CDR regions, such that the obtained structure would result in stable or functional receptors, chains, or fragments thereof. Moreover, there is no disclosed findings or art recognized relationship between T cell receptor structure and function which would allow for the predictable modification of the claimed receptor chains with up to 30% variance anywhere in the structure, particularly in the CDRs, while maintaining the similar characteristics. Therefore, the instant claims are found to not meet the written description requirement.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1 and 4 are rejected under 35 U.S.C. 102(a)(1)(a)(2) as being anticipated by US20210177901 A1 (herein Kuball), published on 17 June 2021, and associated with U.S. Patent No. 12297274.
Kuball teaches γTCR chains comprising CDR3 regions that share at least 60% sequence identity with SEQ ID NO: 1 ([0170]). As shown in the alignment below, SEQ ID NO: 27, referenced by Kuball, shares 100% sequence identity with the reference sequence of instant claim 1. Kuball also teaches that the TCR chains may be soluble ([0127]).
Instant SEQ ID NO:1 1 CATWDGFYYKKLF 13
|||||||||||||
Reference SEQ ID NO:27 1 CATWDGFYYKKLF 13
γTCR chains that share at least 60% sequence identity with the sequence referenced in instant claim 1, SEQ ID NO: 1, and contain modifications to amino acids within the range of positions specified within the claim are taught, shown below (Table 9):
Instant 1 CATWDGFYYKKLF 13 SEQ ID NO: 1 Identity 76.9%
|||||. |||||
Reference 1 CATWDN--YKKLF 11 SEQ ID: 21
Instant 1 CATWDG-FYYKKLF 13 SEQ ID NO: 1 Identity 85.7%
|||||| .||||||
Reference 1 CATWDGPPYYKKLF 14 SEQ ID NO: 19
Instant 1 CATWDGFYYKKLF 13 SEQ ID NO: 1 Identity 76.9%
|||||| .||||
Reference 1 CATWDG--QKKLF 11 SEQ ID: 20
Instant 1 CATWDGFYYKKLF 13 SEQ ID NO: 1 Identity 69.2%
|||||. |.|||
Reference 1 CATWDN--YMKLF 11 SEQ ID NO: 39
Instant 1 CATWD--GFYYKKLF 13 SEQ ID NO: 1 Identity 73.3%
||||| ..||||||
Reference 1 CATWDRPEIYYKKLF 15 SEQ ID NO: 64
Additionally, Kuball teaches a γTCR chain comprising CDR3 region, SEQ ID NO: 34, that share at least 60% sequence identity with SEQ ID NO: 1, that also could be interpreted to contain a phenylalanine to tyrosine amino acid substitution at position 7, relative to the reference sequence (page 29 lines 4-7). As shown in the alignment below, the two CDR3 sequences share 76.9% sequence identity.
Instant SEQ ID NO:1 1 CATWDGFYYKKLF 13 Sequence Identity 76.9%
|||||. |||||
Reference SEQ ID NO:34 1 CATWDN--YKKLF 11
Claims 1, 14, and 15 are rejected under 35 U.S.C. 102(a)(1)(a)(2) as being anticipated by US20190144540 A1 (herein Koide), published on 16 May 2019, and associated with U.S. Patent No. 10519236.
Koide teaches soluble γTCR chains fused to the Fc portion of mouse IgG comprising SEQ ID NO: 39 ([0376]). As shown in the alignments below, SEQ ID NO: 39 shares 98.73% sequence identity with SEQ ID NO: 172 (claim 15) and is comprised of a sequence that shares 98.30% sequence identity with SEQ ID NO: 124 (claim 14) of the instant application. Additionally, the CDR3 region of both chains meet the limitations established in instant claim 1.
Instant SEQ ID NO: 172 SSNLEGRTKSVIRQTGSSAEITCDLAEGSTGYIHWYLHQEGKAPQRLLYYDSYTSSVVLE 60
Reference SEQ ID NO: 39 SSNLEGRTKSVIRQTGSSAEITCDLAEGSTGYIHWYLHQEGKAPQRLLYYDSYTSSVVLE 60
************************************************************
Instant SEQ ID NO: 172 SGISPGKYDTYGSTRKNLRMILRNLIENDSGVYYCATWDAFYYKKLFGSGTTLVVTDKQL 120
Reference SEQ ID NO: 39 SGISPGKYDTYGSTRKNLRMILRNLIENDSGVYYCATWDEKYYKKLFGSGTTLVVTDKQL 120
*************************************** *******************
Instant SEQ ID NO: 172 DADVSPKPTIFLPSIAETKLQKAGTYLCLLEKFFPDVIKIHWEEKKSNTILGSQEGNTMK 180
Reference SEQ ID NO: 39 DADVSPKPTIFLPSIAETKLQKAGTYLCLLEKFFPDVIKIHWQEKKSNTILGSQEGNTMK 180
******************************************:*****************
Instant SEQ ID NO: 172 TNDTYMKFSWLTVPEKSLDKEHRCIVRHENNKNGVDQEIIFPPIKTDVITMDPKDN 236
Reference SEQ ID NO: 39 TNDTYMKFSWLTVPEKSLDKEHRCIVRHENNKNGVDQEIIFPPIKTDVITMDPKDN 236
********************************************************
CDR3 of SEQ ID NO: 172 and 124 CATWDAFYYKKLF 84.6% Sequence IdentityCDR3 of SEQ ID NO: 39 CATWDEKYYKKLF ***** ******
Instant SEQ ID NO: 124 SSNLEGRTKSVIRQTGSSAEITCDLAEGSTGYIHWYLHQEGKAPQRLLYYDSYTSSVVLE 60Reference SEQ ID NO: 39 SSNLEGRTKSVIRQTGSSAEITCDLAEGSTGYIHWYLHQEGKAPQRLLYYDSYTSSVVLE 60 ************************************************************Instant SEQ ID NO: 124 SGISPGKYDTYGSTRKNLRMILRNLIENDSGVYYCATWDAFYYKKLFGSGTTLVVT---- 120Reference SEQ ID NO: 39 SGISPGKYDTYGSTRKNLRMILRNLIENDSGVYYCATWDEKYYKKLFGSGTTLVVTDKQL 120 *************************************** ***************
Double Patenting
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.
Claims 1, 4, 9, 14, 15, 18, 20, 26, 30, 31, 34, 35, and 44-49 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 12-14, 17, and 21 of co-pending Application No. 18/808411 (herein ‘411) in view of Dolgin E. (2022) First soluble TCR therapy opens ‘new universe’ of cancer targets. Nat Biotechnol. 2022 Apr;40(4):441-444 (herein Dolgin). Although the claims at issue are not identical, they are not patentably distinct.
‘411, claims 1-3, describe polypeptide constructs comprising either a γ TCR chain, δ TCR chain, or a γδ TCR or parts thereof. The TCR chains referenced comprise amino acids sequences sharing at least 70% sequence identity or similarity with SEQ ID Nos: 38 and 37. As shown in the alignments below, γ and δ chains disclosed in the instant application are encompassed by the claim limitations established in claim 1 of ‘411. SEQ ID NO: 316 of the instant application, referenced in instant claim 15, comprises amino acid sequences conforming to the limitations established in claims 4, 9, and 14, and shares 88.9% sequence identity to SEQ ID NO: 38 of ‘411. SEQ ID NO: 330 of the instant application, referenced in instant claim 31, comprises amino acid sequences conforming to the limitations established in claims 20, 26, and 30, and shares 90.4% sequence identity to SEQ ID NO: 37 of ‘411. The differences between the two pairs of TCR chains are the result of CDR3 modifications and the removal of the transmembrane domain from the sequences associated with the instant application.
Instant SEQ ID: 316 1 SSNLEGRTKSVIRQTGSSAEITCDLAEGSTGYIHWYLHQEGKAPQRLLYY 50
||||||||||||||||||||||||||||||||||||||||||||||||||
Ref SEQ ID: 38 1 SSNLEGRTKSVIRQTGSSAEITCDLAEGSTGYIHWYLHQEGKAPQRLLYY 50
Instant SEQ ID: 316 51 DSYTSSVVLESGISPGKYDTYGSTRKNLRMILRNLIENDSGVYYCATWDA 100
|||||||||||||||||||||||||||||||||||||||||||||||||.
Ref SEQ ID: 38 51 DSYTSSVVLESGISPGKYDTYGSTRKNLRMILRNLIENDSGVYYCATWDG 100
Instant SEQ ID: 316 101 FYYKKLFGSGTTLVVTDKQLDADVSPKPTIFLPSIAETKLQKAGTYLCLL 150
||||||||||||||||||||||||||||||||||||||||||||||||||
Ref SEQ ID: 38 101 FYYKKLFGSGTTLVVTDKQLDADVSPKPTIFLPSIAETKLQKAGTYLCLL 150
Instant SEQ ID: 316 151 EKFFPDVIKIHWEEKKSNTILGSQEGNTMKTNDTYMKFSWLTVPEKSLDK 200
||||||||||||||||||||||||||||||||||||||||||||||||||
Ref SEQ ID: 38 151 EKFFPDVIKIHWEEKKSNTILGSQEGNTMKTNDTYMKFSWLTVPEKSLDK 200
Instant SEQ ID: 316 201 EHRCIVRHENNKNGVDQEIIFPPIKTDVITMDPKDNCSKDANDTLLLQLT 250
||||||||||||||||||||||||||||||||||||||||||||||||||
Ref SEQ ID: 38 201 EHRCIVRHENNKNGVDQEIIFPPIKTDVITMDPKDNCSKDANDTLLLQLT 250
Instant SEQ ID: 316 251 NTSAYYMY------------------------------- 258 Seq ID 88.9%
||||||||
Ref SEQ ID: 38 251 NTSAYYMYLLLLLKSVVYFAIITCCLLRRTAFCCNGEKS 289
Instant SEQ ID: 330 1 DQQVKQNSPSLSVQEGRISILNCDYTNSMFDYFLWYKKYPAEGPTFLISI 50
||||||||||||||||||||||||||||||||||||||||||||||||||
Ref SEQ ID: 37 1 DQQVKQNSPSLSVQEGRISILNCDYTNSMFDYFLWYKKYPAEGPTFLISI 50
Instant SEQ ID: 330 51 SSIKDKNEDGRFTVFLNKSAKHLSLHIVPSQPGDSAVYFCAASSPIKGFT 100
||||||||||||||||||||||||||||||||||||||||||||||:|:|
Ref SEQ ID: 37 51 SSIKDKNEDGRFTVFLNKSAKHLSLHIVPSQPGDSAVYFCAASSPIRGYT 100
Instant SEQ ID: 330 101 GSDKLIFGKGTRVTVEPRSQPHTKPSVFVMKNGTNVACLVKEFYPKDIRI 150
||||||||||||||||||||||||||||||||||||||||||||||||||
Ref SEQ ID: 38 101 GSDKLIFGKGTRVTVEPRSQPHTKPSVFVMKNGTNVACLVKEFYPKDIRI 150
Instant SEQ ID: 330 151 NLVSSKKITEFDPAIVISPSGKYNAVKLGKYEDSNSVTCSVQHDNKTVHS 200
||||||||||||||||||||||||||||||||||||||||||||||||||
Ref SEQ ID: 38 151 NLVSSKKITEFDPAIVISPSGKYNAVKLGKYEDSNSVTCSVQHDNKTVHS 200
Instant SEQ ID: 330 201 TDFEVKTDSTDHVKPKETENTKQPSKSCHKPKAIVHTEKVNMMSLTV--- 247
|||||||||||||||||||||||||||||||||||||||||||||||
Ref SEQ ID: 38 201 TDFEVKTDSTDHVKPKETENTKQPSKSCHKPKAIVHTEKVNMMSLTVLGL 250
Instant SEQ ID: 330 248 --------------------- 247 Seq ID 90.4%
Ref SEQ ID: 38 251 RMLFAKTVAVNFLLTAKLFFL 271
The removal of the transmembrane domain is what allows the TCR chains/receptors disclosed in the instant application to exist in a soluble state, and is not taught in the claims of ‘411. Dolgin teaches this deficiency.
Dolgin teaches several advantages associated with the use of soluble TCR for the treatment of cancer. One such advantage is the lack of chemotherapy “pre-conditioning”, typically required for adoptive therapy, which would allow for a ready-made treatment (page 442 paragraph 3). Another major advantage, associated with the ready-made nature of soluble receptor compositions, is the relative simplicity of the treatment compared to autologous adoptive T cell therapies, which require individualized therapeutic manufacturing (page 442 paragraph 2). Additionally, it is taught that the use of soluble receptors allows for increased flexibility in receptor design, which is highlighted by the author’s acknowledgement of designs that convey functional features, such as increased serum half-life of the receptors, through the use of either peptide designs that include silenced Fc domains or an albumin-targeted antigen binding domain, or immune modulators, as exemplified by the use of CD3-targeted antigen binding domains (page 442 paragraph 8, page 443 paragraph 1. Figure 1, page 441 paragraph 5).
It would have been obvious to one of ordinary skill in the art to combine the teachings of Dolgin with the TCR chains/receptors described in claims 1-3 of application 18/808411. An ordinarily skilled artisan would have been motivated to modify the TCR chains/receptors to exist in a soluble state, because of the benefits taught by Dolgin, such as increased design/functional flexibility and simplified treatment protocol. Furthermore, by combining these pre-existing elements, the instant application discloses a claimed invention that behaves in a predictable manner, based on the prior art describing each element individually.
In regard to claims instant claims 34 and 35, the sequence alignment shown above demonstrates that the δ and γ TCR chains limitations established in these claims are encompassed by the claim limitations established in claims 1-3 of ‘411.
In regard to claims 44 and 45 of the instant application, the nucleic acid molecule/construct described in this claim is effectively encompassed by claims 4 of ‘411.
In regard to claims 46 and 47 of the instant application, the cell described in these claims is effectively encompassed by claim 7 of ‘411.
In regard to claims 48 and 49 of the instant application, claims 12 and 13 of ‘411 encompass instant claim 48 and claims 14, 15, and 17 of ‘411 encompass instant claim 49.
This is a provisional non-statutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATTHEW CURRAN METCALF whose telephone number is (571)272-5520. The examiner can normally be reached 7:30AM-5:00PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached at (571)272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/MATTHEW CURRAN METCALF/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647