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 .
Status of the Application
Claims 19 and 31-43 are cancelled. Claims 44-55 are pending.
Claims 44-51 and 53-55 are withdrawn as being drawn to non-elected inventions based on election by original presentation, as discussed below.
Claim 52 is under examination.
Election by Original Presentation
Newly submitted claims 44-55 are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons:
Claims 44-50, i.e. Group I, are drawn to a library of particles displaying a plurality of T cell receptors (TCRs); a T cell receptor and a particle displaying a TCR.
Claim 51, i.e. Group II, are drawn to a nucleic acid encoding the TRAV12-2 or TRAV21 alpha chain variable domain and/or the TRBV6 beta chain variable domain.
Claims 52, i.e. Group III, are drawn to a method of obtaining a TCR that specifically binds a peptide antigen.
Claims 53-55, i.e. Group IV, are drawn to a method of making a library of particles.
The inventions are independent or distinct, each from the other because:
Inventions of Group I and Groups III/IV are related as product and processes of use.
The inventions can be shown to be distinct if either or both of the following can be shown: (1) the process for using the product as claimed can be practiced with another materially different product or (2) the product as claimed can be used in a materially different process of using that product. See MPEP § 806.05(h). In the instant case, the library of Group I can be used for other analysis. For example, the library of Group I can be used to capture small molecules conjugated to TCR targets.
Inventions of Group I and Group II are directed to related products. The related inventions are distinct if: (1) the inventions as claimed are either not capable of use together or can have a materially different design, mode of operation, function, or effect; (2) the inventions do not overlap in scope, i.e., are mutually exclusive; and (3) the inventions as claimed are not obvious variants. See MPEP § 806.05(j). In the instant case, the inventions as claimed have a materially different design. For example, the nucleic acid of Invention II may encode for a specific TRAV domain OR a specific TRBV domain, but does not require both domains. Furthermore, the inventions as claimed do not encompass overlapping subject matter and there is nothing of record to show them to be obvious variants.
Inventions of Group III and Group IV are directed to related processes. The related inventions are distinct if: (1) the inventions as claimed are either not capable of use together or can have a materially different design, mode of operation, function, or effect; (2) the inventions do not overlap in scope, i.e., are mutually exclusive; and (3) the inventions as claimed are not obvious variants. See MPEP § 806.05(j). In the instant case, the inventions as claimed have materially different design. For example, the method of the Invention of Group IV does not require binding to a peptide antigen target. Furthermore, the inventions as claimed do not encompass overlapping subject matter and there is nothing of record to show them to be obvious variants.
Since applicant has received an action on the merits for the originally presented invention, i.e. a method of obtaining a T cell receptor that specifically binds a peptide antigen, as recited in now cancelled claims 19-31 and 43, the invention comprising claim 52 has been constructively elected by original presentation for prosecution on the merits.
Regarding interpretation of claim 52, art is applied that meets the requirements of the originally presented invention, i.e. the embodiment comprising a method comprising providing libraries of particles displaying T cell receptors; providing constructs consisting essentially of alpha chain variable domain selected from a TRAV21 gene product from a natural repertoire and a beta chain variable domain selected from a TRBV6 gene product from a natural repertoire and screening binding over multiple rounds and providing a natural repertoire of TCRs that have undergone thymic selection in a human donor.
Accordingly, claims 44-51 and 53-55 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Claim Rejections - 35 USC § 103
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.
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.
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.
Jakobsen I, Boulter et al., and Plum et al.
Claim 52 is rejected under 35 U.S.C. 103 as being unpatentable over Jakobsen et al. (US2010113300), i.e. Jakobsen I, in view of Boulter et al. (WO20050116074) and Plum et al.("Human intrathymic development: a selective approach." Seminars in immunopathology. Vol. 30. No. 4. Springer-Verlag, 2008).
Jakobsen I teach using particles displaying recombinant TCR for biopanning comprising binding with peptide-HLA molecules (e.g. Such proteinaceous particle-displayed TCRs are useful for purification and screening purposes, particularly as a diverse library of particle displayed TCRs for biopanning to identify TCRs with desirable characteristics as in para 0046, pg. 4; 0097, pg. 8; binding to peptide-HLA molecules as in Example 18-19, 22 and 23, pg. 25-27).
Furthermore, Jakobsen I teach providing libraries of particles, such as phages, displaying T cell receptors, i.e. TCRs, comprising single chain TCR, i.e. scTCR, or dimeric TCR, i.e. dTCR, wherein the constructs comprise a disulfide linker to connect alpha variable chain to beta variable chain (e.g. diverse library as in para 0046, pg. 4; para 0122, pg.10; para 0048-0061, pg. 4-5; Example 6, pg. 19).
Furthermore, Jakobsen I teach an embodiment wherein the amino acid sequences of variable chains of their TCR molecules correspond to the reference sequence in the native human TCR and the disulfide linker does not have a native equivalent (e.g. TCR is a scTCR polypeptide comprising TCR amino acid sequences corresponding to extracellular constant and variable domain sequences present in native TCR chains and a linker sequence, the latter linking a variable domain sequence corresponding to that of one chain of a native TCR to a constant domain sequence corresponding to a constant domain sequence of another native TCR chain, and a disulfide bond which has no equivalent in native T cell receptors links residues of the constant domain sequences as in para 0051, pg. 4; In one preferred embodiment, the invention provides A proteinaceous particle, displaying on its surface a dimeric I-cell receptor (dTCR) polypeptide pair, or a single chain I-cell receptor (scTCR) polypeptide wherein the dTCR polypeptide pair is constituted by TCR amino acid sequences corresponding to extracellular constant and variable domain sequences present in native TCR chains, and the scTCR is constituted by TCR amino acid sequences corresponding to extracellular constant and variable domain sequences present in native TCR chains and a linker sequence, the latter linking a variable domain sequence corresponding to that of one chain of a native TCR to a constant domain sequence corresponding to a constant domain sequence of another native TCR chain; wherein the variable domain sequences of the dTCR polypeptide pair or scTCR polypeptide are mutually orientated substantially as in native TCRs as in para 0052,pg. 4).
Jakobsen I teach a native or non-native disulfide bond is included in dimeric or single chain constructs (e.g. para 0090, pg. 7).
Jakobsen I teach the TCRs are displayed on particles such as ribosomes (e.g. para 0114, pg. 9-10), phage particles (e.g. in para 0046, pg. 4; para 0122, pg.10; para 0048-0061, pg. 4-5; Example 6, pg. 19), yeast cells and mammalian cells (e.g. para 0028-0041, pg. 2-4).
Jakobsen I also teach an alternative embodiment comprising providing “high affinity” TCRs by generating TCRs comprising mutated alpha and beta chains which facilitate higher binding affinity (e.g. The present invention also makes available mutated TCRs specific for a given TCR ligand with higher affinity for said TCR ligand than the wild-type TCR as in para 0132, pg. 11; para 0133, pg. 11; Example 8, pg. 20-22).
Jakobsen I teach providing a library comprising T cell receptors derived from a nucleic acid sequence comprising TRAV21 nucleic acid sequence and TRBV6 nucleic acid sequence. Furthermore, the TRBV6 nucleic acid sequences include TRBV6-1/2/3/5/6/7/8/9 (e.g. Example 12, pg. 24).
Regarding the embodiment comprising a method comprising providing constructs consisting essentially of alpha chain variable domain selected from a TRAV21 gene product from a natural repertoire and a beta chain variable domain selected from a TRBV6 gene product from a natural repertoire and screening binding over multiple rounds:
As noted above, Jakobsen I teach methods of screening binding of TCR using peptide HLA ligands through biopanning to identify TCRs with desirable characteristics , wherein their methods comprise providing TCR constructs derived from nucleic acid sequences of native TCR variable chains (e.g. para 0051-0052, pg. 4) as well as providing a library derived from nucleic acid sequences comprising TRAV21 nucleic acid sequence and TRBV6 nucleic acid sequence.
Prior to the effective filing date of the claimed invention, Boulter et al. teach methods comprising providing TCR libraries comprising constructs of native TCR alpha and beta variable chain sequences are known in the art (e.g. In the present invention the displayed TCRs comprise native variable domains attached to the nucleoprotein of choice, which is preferably a ribosome or phage particle, and most preferably a phage particle… The present invention make available for the first time libraries containing a diverse array of native TCR variable domains displayed on the surface of nucleoproteins as in lines 8-12, pg. 12; lines 7-11, pg. 13; generation of V and V chains by cDNA synthesis and cloning into an expression vector as in lines 17-30,pg. 28- lines 1-19, pg. 30).
Furthermore, Boulter et al. teach their methods comprise screening phage-associated TCR molecules by biopanning by subjecting the TCR molecules to multiple rounds of binding with peptide-HLA molecules (e.g. multiple rounds of screening by binding as in lines 4-15, pg. 7; lines 24-31, pg. 11- lines 1-6,pg. 12; lines 26-31,pg. 24- lines 1-14, pg. 25; The isolation of TCRs that bind to a target peptide-MHC complex from the diverse phage library displaying native TCR variable domains described above was carried out as follows. The initial panning was carried utilising the selection of phage particles (prepared as described above) displaying native TCR variable domains) as in lines 14-17, pg. 36; Phage particles, displaying native TCR variable domains at a concentration of 1012 to 1013 cfu in 3% powdered milk- PBS, were pre-mixed with biotinylated SLLMWITQC-HLA-A*0201 at a concentration of 500nM for all three rounds of selection carried out as in lines 20-23, pg. 36; After the third round of selection, 100 colonies were picked from either the SLLMWITQC-HLA-A *0201 complex plates and used to inoculate 100 μ1 of 2TYAG in a 96-well microtiter plate as in lines 5-7,pg. 37; screening and identification as in Example 2, pg. 36-41).
Regarding the embodiment comprising a method comprising providing a natural repertoire of TCRs that have undergone thymic selection in a human donor:
Prior to the effective filing date of the claimed invention, Plum et al. teach that it is known in the art that positive thymic selection of human T cells is essential to provide a functional MHC-restricted naive repertoire of TCR molecules (e.g. 1st para, Introduction section, pg. 411).
Therefore, as Jakobsen I, Boulter et al. and Plum et al. all teach providing functional TCR molecules and Jakobsen I and Boulter et al. both teach methods comprising screening TCR for binding, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the method of Jakobsen I comprising screening TCR products comprising the alpha chain variable domain comprising a TRAV21 gene product and the beta chain variable domain comprising a TRBV6 gene product expressed from polynucleotides that are derived from native sequences to include native TCR alpha and beta variable chain sequences as occurs in naturally-occurring TCR molecules wherein screening comprises biopanning over multiple rounds using peptide-HLA molecules as taught by Boulter et al. wherein the naturally-occurring TCR molecules are obtained from a functional, MHC-restricted repertoire from human T cells resulting from positive thymic selection as taught by Plum et al. because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a method of screening a library of particles displaying a plurality of TCR molecules using peptide –HLA molecules.
It is noted that the instant specification describes peptide HLA molecules as pHLA (e.g. para 0161, pg. 34-35, instant specification).
Therefore, the combined teachings of Jakobsen I, Boulter et al. and Plum et al. render obvious 52.
Response to the Arguments
Any rejection not reiterated or specifically addressed has been overcome by amendment. New rejections are set forth to address the amended claims.
However, previously cited references teach art relevant to the amended claims and therefore are included in the new rejections.
Regarding Applicants’ arguments that the previously cited art does not meet the requirements of the amended claims: these arguments are not persuasive.
As discussed above, claim 52 is elected by original presentation and claims 44-51 and 53-55 are withdrawn as being drawn to non-elected inventions.
Regarding interpretation of claim 52, art is applied that meets the requirements of the originally presented invention, i.e. the embodiment comprising a method comprising providing a library of particles displaying T cell receptors; providing constructs consisting essentially of alpha chain variable domain selected from a TRAV21 gene product from a natural repertoire and a beta chain variable domain selected from a TRBV6 gene product from a natural repertoire and screening binding over multiple rounds and providing a natural repertoire of TCRs that have undergone thymic selection in a human donor.
Conclusion
No claims are allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAHANA S KAUP whose telephone number is (571)272-6897. The examiner can normally be reached on M-F 7-10 EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, HEATHER CALAMITA can be reached on 571-272-2876. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SAHANA S KAUP/ Primary Examiner, Art Unit 1684