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 .
Claim Status
Claims 1-21 are cancelled by Applicant.
Claims 22-41 are newly added by Applicant.
Claims 22-41 are currently pending and are herein under examination.
Claims 22-41 are rejected.
Claims 22, 24-25 and 31 are objected.
Priority
The instant application claims domestic benefit as a divisional to US Application No. 16/692,544, filed on November 22, 2019, which is a continuation of US Application No. 16/484,918, filed August 9, 2019, which is a US National Stage entry of International Application No. PCT/US2018/017849, filed February 12, 2018, which claims domestic benefit to US Provisional Application No. 62/457,978, filed February 12, 2017 and US Provisional Application No. 62/461,162, filed February 20, 2017. The claims to domestic benefit are acknowledged. As such, the effective filing date for claims 22-41 is February 12, 2017.
Information Disclosure Statement
The IDS filed on 08/16/2023 and 03/18/2025 follow the provisions of 37 CFR 1.97 and have been considered in full. A signed copy of the list of references cited from these IDS is included with this Office Action.
Abstract
The abstract of the disclosure is objected to because it contains less than 50 words. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
Drawings
The drawings filed 03/28/2023 are accepted.
Nucleotide and/or Amino Acid Sequence Disclosures
The Sequence Listing filed 03/28/2023 is in accordance with 37 CFR 1.831.
Claim Objections
Claims 22, 24-25 and 31 are objected to because of the following informalities:
Claim 22, line 14, should recite “the MHC-peptide presentation prediction algorithm” to maintain consistent claim terminology.
Claim 24 should recite “the affinity acceptor peptide sequence” to maintain consistent claim terminology.
Claim 25, line 1, should recite “the affinity acceptor peptide sequence binding molecule” to clarify antecedent basis to the affinity molecule that binds the affinity acceptor peptide sequence in claim 22, step b.
Claim 25, line 2, should recite “the affinity acceptor peptide sequence” to maintain consistent claim terminology.
Claim 31, line 6, recites “TAP” which should be spelled out.
Claim 31, line 6, recites “host protein is subject to autophagy” which appears that is should recite “host protein that is subject to autophagy”.
Appropriate correction is required.
Claim Interpretation
Claim 22, step aii, is an optional limitation and thus is not required (MPEP 2111.04.I). Claim 22, steps b – d, are contingent upon step aii because step b requires the MHC be linked to the affinity acceptor peptide sequence recited in step aii. If step aii is not selected, then b is not performed because there is no acceptor peptide sequence. Subsequently, steps c – d are not performed either because they are contingent upon step b. MPEP 2111.04(II) recites “[t]he broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met.” As such, claim 22, steps c – d, are not required.
The BRI of claim 22 requires only steps a – ai. Claims 23-26, 31-33 and 36 are also not required because they further limit claim 22, steps aii – d, which are not required.
Claim Rejections - 35 USC § 112
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 22-40 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 dependent from a rejected claim are also rejected, unless otherwise noted.
Claim 22, lines 5, 8, 11 and 14, recites “the recombinant MHC protein” which renders the claim indefinite. It is unclear which MHC protein is being referenced because line 4 recites that each training cell expresses a recombinant MHC protein. Clarify which recombinant MHC protein is being referenced.
Claim 22, lines 5 and 7, recites “the training cell” which renders the claim indefinite. It is unclear which training cell is being referenced because line 3 recites a plurality of training cells. Clarify which training cell is being referenced.
Claim 23 recites “the recombinant MHC protein” which renders the claim indefinite. It is unclear which MHC protein is being referenced because claim 22, line 4, recites that each training cell expresses a recombinant MHC protein. Clarify which recombinant MHC protein is being referenced.
Claim 27 recites “the MHC protein” which renders the claim indefinite. It is unclear which MHC protein is being referenced because claim 22, step a, recites that each cell has a recombinant MHC protein and claim 22, step aii, recites “an endogenous MHC protein”. Clarify which MHC protein is being referenced.
Claim 30 recites “the training cell” which renders the claim indefinite. It is unclear which training cell is being referenced because in claim 22, line 3, recites a plurality of training cells. Clarify which training cell is being referenced.
Claim 31, line 3, recites “the source protein of the peptide” which lacks antecedent basis. Provide antecedent basis.
Claims 35 and 40 recite “the recombinant MHC protein” which renders the claim indefinite. It is unclear which MHC protein is being referenced because claim 22, line 4, recites that each training cell expresses a recombinant MHC protein. Clarify which recombinant MHC protein is being referenced.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 37-38 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Step 1:
Step 1 asks whether the claims recite statutory subject matter. In the instant application, claims 37-38 recite a method. As such, these claims recite statutory subject matter (Step 1: YES).
Step 2A, Prong 1:
Claims that recite statutory subject matter are analyzed under Step 2A, Prong 1 to determine if they recite any concepts that equate to an abstract idea, law of nature or natural phenomena. The instant claims recite the following limitations that equate to one or more categories of judicial exception:
Claim 37 recites “generating an HLA-allele specific binding peptide sequence database for a plurality of HLA alleles.”
Claim 38 recites “further comprising generating a peptide library comprising peptides associated with a disease prior to immunoprecipitating.”
Limitations reciting a mental process.
Claims 37-38 are recited at such a high level of generality that they equate to mental processes because they’re similar to the concept of collecting information, analyzing it, and displaying certain results of the collection and analysis in Electric Power Group, LLC, v. Alstom (830 F.3d 1350, 119 USPQ2d 1739 (Fed. Cir. 2016)), which the courts have identified as mental process. The BRI of claims 37-38 includes using pen and paper to write down known peptide sequences collected from online databases. This interpretation is reinforced by the fact that the database/library is not stored in memory nor is there a requirement for synthesizing the peptides.
As such, claims 37-38 recite an abstract idea (Step 2A, Prong 1: YES).
Additional Elements:
Once limitations have been identified that recite a judicial exception, the claims are evaluated for additional elements. The additional elements are then analyzed under Step 2A, Prong 2 then Step 2B. The instant claims recite the following additional elements:
Claim 22 recites “(a) contacting a plurality of training peptides with a plurality of training cells in vitro, wherein each training cell of the plurality of training cells expresses a recombinant MHC protein, and wherein the recombinant MHC protein incorporates into a cell membrane of the training cell, and (i) wherein the training cell does not express an endogenous MHC protein.”
Claim 22 is analyzed under Step 2A, Prong 2 and Step 2B despite reciting only additional elements because dependent claims 37-38 recite a judicial exception. It is understood that claim 22 is not rejected under 35 USC 101. As discussed in Claim Interpretation, claim 22, steps aii – d, are not required. Thus, claim 22 steps a – ai are being analyzed in claim 22.
Step 2A, Prong 2:
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). The judicial exception is not integrated into a practical application because the claims do not recite additional elements that reflect an improvement to a computer, technology, or technical field (MPEP § 2106.04(d)(1) and 2106.5(a)), require a particular treatment or prophylaxis for a disease or medical condition (MPEP § 2106.04(d)(2)), implement the recited judicial exception with a particular machine that is integral to the claim (MPEP § 2106.05(b)), effect a transformation or reduction of a particular article to a different state or thing (MPEP § 2106.05(c)), nor provide some other meaningful limitation (MPEP § 2106.05(e)). Rather, the claims include limitations that equate to insignificant extra-solution activity (MPEP § 2106.05(g)).
Claim 22, steps a – ai, equate to insignificant, extra-solution activity because they gather data and are nominally related to the recited judicial exception in claims 37-38.
As such, claims 37-38 are directed to an abstract idea (Step 2A, Prong 2: NO).
Step 2B:
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). These claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because these claims recite additional elements that equate to well-understood, routine and conventional (WURC) limitations (MPEP § 2106.05(d)).
When the additional elements of claim 22 are viewed alone and in combination, they equate to WURC limitations as taught below by Kropshofer et al. (“Kropshofer”; US 2004/0086521 A1), Yelensky et al. (“Yelensky”; US 2017/0199961 A1), and Rosskopf et al. (“Rosskopf”; Scientific reports 6, no. 1 (2016): 31580).
Kropshofer purifies MHC-peptide complexes from antigen presenting cell (APC) lysates using immunoprecipitation then identifies the peptides by mass spectrometry (Figure 2A) [39-41]. The APCs express transfected HLA-DR rather than expressing MHC endogenously [84] [153]. Cells are exposed to synthetic or endogenous antigens [28] (claim 18).
Yelensky uses training data comprising peptide sequences present in samples and one or more MHC alleles associated with each training peptide sequence [108]. The samples are cell lines engineered to express a single predetermined MHC class I or II allele [109]. The MHC alleles are exposed to synthetic proteins [93]. Cells are lysed then immunoprecipitated and mass spectrometry identifies the proteins [295]. The number of MHC allele types can be in the hundreds [364].
Rosskopf creates engineered antigen presenting cells (eAPCs) and exposes them to allergen peptides (abstract). The eAPCs contain transfected constructs of HLAs (pg. 13, para. 4) (Figure 1). eAPCs are derived from K562 cell lines that are devoid of endogenous class I and II HLAs (pg. 1, para. 2).
When these additional elements are considered individually and in combination, they do not provide an inventive concept because they equate to WURC limitations as taught above by Kropshofer, Yelensky and Rosskopf. Therefore, these additional elements do not transform the claimed judicial exception into a patent-eligible application of the judicial exception and do not amount to significantly more than the judicial exception itself (Step 2B: No).
As such, claims 37-38 are not patent eligible.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 22-28, 30-34, 36, 38 and 41 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Rosskopf et al. (“Rosskopf”; Scientific reports 6, no. 1 (2016): 31580).
The bold and italicized text below are the limitations of the instant claims, and the italicized text serves to map the prior art onto the instant claims.
Claim 22:
(a) contacting a plurality of training peptides with a plurality of training cells in vitro,
Rosskopf creates engineered antigen presenting cells (eAPC) to optimize presentation of immunodominant peptides of major allergens (abstract). The eAPCs were loaded with exogenous allergenic peptides (abstract).
wherein each training cell of the plurality of training cells expresses a recombinant MHC protein, and wherein the recombinant MHC protein incorporates into a cell membrane of the training cell,
Rosskopf recites “[r]etroviral expression constructs encoding HLA-DMα ; HLA-DMβ , HLA-DOα ; HLA-DOβ , HLA-DRA, HLA-DRB1* 01:01, HLA-DRB1* 07:01 and Cathepsin S were generated by excising the cDNAs encoding these molecules from pEAK12 expression plasmids and cloning them into the retroviral vector pCJK2 … eAPC expressing HLA-DRB1* 01:01, HLA-DRB1* 03:01 and HLA-DRB1* 07:01 were generated by coexpressing HLA-DRα and the respective HLA-DR-β -chain. In addition, eAPC coexpressing HLA-DRB1* 01:01, HLA-DRB1* 03:01 and HLA-DRB1* 07:01 with CD80 were generated” (pg. 13, para. 4-5). Figure 1A shows a recombinant MHC molecule on cell surface of K562 cells.
and (i) wherein the training cell does not express an endogenous MHC protein, or
The eAPCs are generated from human erythroleukemia cell line K562 which are devoid of endogenously expressed MHC class I and II molecules (pg. 1, para. 2).
(ii) wherein the recombinant MHC protein is linked to an affinity acceptor peptide sequence; (b) immunoprecipitating the plurality of training cells with an affinity molecule that binds to the affinity acceptor peptide sequence, thereby obtaining immunoprecipitated training cells; (c) identifying training peptides bound to the recombinant MHC protein of the immunoprecipitated training cells by mass spectrometry; and (d) inputting as a variable information on the training peptides identified by mass spectrometry and information on the recombinant MHC protein into the presentation prediction algorithm, thereby training the MHC-peptide presentation prediction algorithm.
As discussed in Claim Interpretation, steps aii – d are not required by the claim and thus are not being examined under 35 USC 102.
Claim 23-26, 31-33 and 36:
As discussed in Claim Interpretation, claims 23-26, 31-33 and 36 are contingent upon claim 22, step aii, which is not required by claim 22. As such, these claims are rejected for being dependent on rejected claim 22.
Claims 27-28:
Figure 1A shows K652 cells with a single allergen specific recombinant MHC class II molecule.
Claim 30:
Rosskopf uses K652 cell line that are modified to become engineered antigen presenting cells (abstract).
Claim 34:
Rosskopf recites “we used Bet v 1 as model allergen to study the ability of K562 cells to present antigenic peptides derived from whole proteins either taken up or endogenously expressed as LAMP-1 fusion protein” (abstract) (pg. 1, para. 2).
Claim 38:
Allergens Bet v 1 and Art v1 peptides were previously generated and bought from Thermo Fisher (pg. 13, para. 2).
Claim 41: Rosskopf recites “[r]etroviral expression constructs encoding HLA-DMα ; HLA-DMβ , HLA-DOα ; HLA-DOβ , HLA-DRA, HLA-DRB1* 01:01, HLA-DRB1* 07:01 and Cathepsin S were generated by excising the cDNAs encoding these molecules from pEAK12 expression plasmids and cloning them into the retroviral vector pCJK2 … eAPC expressing HLA-DRB1* 01:01, HLA-DRB1* 03:01 and HLA-DRB1* 07:01 were generated by coexpressing HLA-DRα and the respective HLA-DR-β -chain … Single cell clones were established after each transduction step to assure homogenous and comparable expression of the respective molecules” (pg. 13, para. 4-5) (a library of cells, each cell of the library expressing a different recombinant MHC protein encoded by an expression vector). Figure 1A shows K652 cells with a single MHC class II molecule on cell surface of K652 cell (wherein each recombinant MHC protein incorporates into a cell membrane of the cells). The eAPCs are generated from human erythroleukemia cell line K562 which are devoid of endogenously expressed MHC class I and II molecules (pg. 1, para. 2) (each cell of the cell library does not express an endogenous MHC protein).
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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 22-28 and 30-39 are rejected under 35 USC 103 for being unpatentable over Yelensky et al. (“Yelensky”; US 2017/0199961 A1; effective filing date 23 Nov. 2016) in view of Duffy et al. (“Duffy”; Analytical biochemistry 262, no. 2 (1998): 122-128).
The bold and italicized text below are the limitations of the instant claims, and the italicized text serves to map the prior art onto the instant claims.
Claim 22:
A method for training an MHC-peptide presentation prediction algorithm implemented in a computer processor, comprising:
Yelensky trains a presentation model that generates a dependency score indicating whether one or more MHC alleles will present a neoantigen [93] [100].
(a) contacting a plurality of training peptides with a plurality of training cells in vitro, wherein each training cell of the plurality of training cells expresses a recombinant MHC protein, and wherein the recombinant MHC protein incorporates into a cell membrane of the training cell,
Yelensky uses training data comprising peptide sequences present in samples and one or more MHC alleles associated with each training peptide sequence [108]. The samples are cell lines engineered to express a single predetermined MHC class I or II allele [109]. The MHC alleles are exposed to synthetic proteins [93]. The MHC molecule is located at the cell surface [229].
(ii) wherein the recombinant MHC protein is linked to an affinity acceptor peptide sequence; (b) immunoprecipitating the plurality of training cells with an affinity molecule that binds to the affinity acceptor peptide sequence, thereby obtaining immunoprecipitated training cells;
Claim 22, step ai, is not required by the claim and is not being analyzed under 35 USC 103.
Regarding, claim 22, step aii, Yelensky isolates HLA peptides by using immunoprecipitation with antibodies coupled to beads, wherein the antibody is specific for HLA class I or II [295-296].
However, Yelensky does not teach that the engineered cell lines expressing a single predetermined MHC allele are linked to an affinity acceptor peptide sequence that is then bound by an affinity molecule.
Duffy discloses site-specific, enzymatic biotinylation of recombinant proteins linked with a biotin acceptor peptide sequence (affinity acceptor peptide sequence) using biotin holoenzyme synthetase for immobilization on streptavidin-coated surfaces (affinity molecule) (title) (pg. 126, col. 2, para. 4). Figure 1 shows recombinant vector bDW449 that produces both E. coli BirA and an MBP-Raf fusion protein with a BAP joined to its N-terminus (BAP-MBP-Raf).
It would have been prima facie obvious to have linked Yelensky’s engineered single MHC allele cell lines with a BAP so that the MHC protein can be biotinylated then purified as taught by Duffy. The motivation for doing so is that biotinylation ensures that all molecules are immobilized in the same orientation, resulting in highest possible specific activity (pg. 122, col. 2, para. 2). Duffy also states that biotinylation has advantages as a general method for affinity purification of proteins (pg. 126, col. 2, last para. 2). There would have been a reasonable expectation of success to link a BAP to an MHC allele and purify it because Duffy recites that biotin acts as an affinity handle to purify a biotinylated protein and that nearly all proteins can be elongated at either end without comprising biological activity (pg. 123, col. 1, para. 2) (pg. 126, col. 2, last para.) (pg. 128, col. 1, para. 1). Thus, one of skill would expect that an MHC allele can be modified to contain a BAP and be purified.
(c) identifying training peptides bound to the recombinant MHC protein of the immunoprecipitated training cells by mass spectrometry; and
Yelensky identifies peptides from immunoprecipitated HLA-peptide complexes by mass spectrometry [198] [297-298].
(d) inputting as a variable information on the training peptides identified by mass spectrometry and information on the recombinant MHC protein into the presentation prediction algorithm, thereby training the MHC-peptide presentation prediction algorithm.
Yelensky trains the presentation model using data derived from HLA-peptide complexes measured from immunoprecipitation and mass spectrometry [93] [294-298].
Claims 23-26:
Yelensky discloses engineered cell lines expressing a single predetermined MHA allele [93]. HLA-peptide molecules were immunoprecipitated using antibodies coupled to NHS-sepharose beads, wherein the antibodies are specific for HLA class I or II alleles [295-297].
However, Yelensky does not teach that the MHC allele is linked to a BAP that is bound to an affinity molecule, nor an affinity acceptor peptide specific binding molecule.
Duffy discloses site-specific, enzymatic biotinylation of recombinant proteins linked with a BAP (affinity acceptor peptide sequence) using biotin holoenzyme synthetase for immobilization on streptavidin-coated surfaces (the affinity molecule is streptavidin) (title) (pg. 126, col. 2, para. 4). Figure 1 shows recombinant vector bDW449 that produces both E. coli BirA and an MBP-Raf fusion protein with a BAP joined to its N-terminus (BAP-MBP-Raf).
When Yelensky and Duffy are taken together, they teach biotinylating MHC cell surface proteins linked with a BAP (the affinity acceptor peptide specific binding molecule is biotin; affinity acceptor peptide sequence is operably linked to an extracellular portion of the recombinant MHC protein).
It would have been prima facie obvious to have linked Yelensky’s engineered single MHC allele cell lines with a BAP so that the MHC protein can be biotinylated and immobilized on a streptavidin coated surface for affinity purification as taught by Duffy. The motivation for doing so is that biotinylation ensures that all molecules are immobilized in the same orientation, resulting in highest possible specific activity (pg. 122, col. 2, para. 2), and biotinylation has advantages as a general method for affinity purification of proteins (pg. 126, col. 2, last para. 2). There would have been a reasonable expectation of success because Duffy recites that the method is used for protein purification, and nearly all proteins can be modified using their method because proteins can be elongated at either end without comprising biological activity (pg. 123, col. 1, para. 2) (pg. 126, col. 2, last para.) (pg. 128, col. 1, para. 1).
Claims 27-28:
Yelensky recites the “samples can also include cell lines engineered to express a single MHC class I or class II allele” [109].
Claim 30:
Yelensky teaches the samples cells as dendritic cells [95].
Claim 31:
Yelensky teaches the training data contains data associated with peptide-MHC binding affinity/stability measurements for the isolated peptides (protein stability) [121-122].
Claims 32-33:
Claims 33-33 are not required because they further limit optional limits recited in claim 31 that were not selected. As such, claims 32-33 are rejected for their dependency on rejected claim 31.
Claim 34:
Yelensky teaches endogenously expressed neoantigens may be identified by mass spectrometry from isolated peptides eluted from MHC complexes (claim 77).
Claim 35:
Yelensky discloses engineered cell lines expressing a one or more MHC alleles [109-110]. The number of unique allele types can be in the hundreds [364].
Claim 36:
Yelensky teaches that the training data comprises “mass spectrometry data, sequencing data, RNA sequencing data, and proteomics data for single-allele cell lines engineered to express a predetermined MHC allele that are subsequently exposed to synthetic protein” [159].
Claim 37:
Yelensky discloses the IEDB database which contains single-allele mass spectrometry data for a variety of MHC alleles [469] [483]. Alternatively, the presentation models generate likelihoods of whether a given peptide sequence will be presented for a set of associated MHC alleles and are stored in presentation information 165 (Figure 2A) [303].
Claim 38:
Yelensky teaches that neoantigenic peptides libraries can be synthesized [211] [215].
Claim 39:
Yelensky teaches that immunoprecipitation was performed after lysis of cell samples [295].
Claim 29 is rejected under 35 USC 103 for being unpatentable over Yelensky et al. (“Yelensky”; US 2017/0199961 A1; effective filing date 23 Nov. 2016) in view of Duffy et al. (“Duffy”; Analytical biochemistry 262, no. 2 (1998): 122-128) and in further view of Li et al. (“Li”; Analytical chemistry 80, no. 18 (2008): 7068-7074).
The limitations of claim 22 are taught above by Yelensky and Duffy.
Claim 29:
Yelensky discloses engineered cell lines expressing a one or more MHC alleles (a first/second MHC molecule) [93] [109-110]. However, Yelensky and Duffy do not teach that each recombinant MHC protein contains distinct affinity acceptor peptide sequences.
Li discloses multiplexed affinity-based protein complex purification (MAPcP) targets simultaneous extraction of multiple protein complexes (abstract). Protein A and GFP (a first/second affinity acceptor peptide) were used as two distinct affinity tags for immunoprecipitation of two immuno-complexes by MAPcP (pg. 7070, col. 1, para. 2) (pg. 7071, col. 2, last para.) (Figure 3).
It would have been prima facie obvious to have modified the immunoprecipitation of Yelensky to use the MAPcP technique of Li that uses different affinity tags for each recombinant protein. Motivation for doing so is that MAPcP provides superior purity for simultaneous extraction of multiple protein complexes when compared to traditional centrifugation and magnetic pull-down methods, as taught by Li (abstract) (pg. 7069, col. 1, last para.). Also, by isolating multiple proteins in one preparation, variation in using different processes is eliminated, as taught by Li (pg. 7073, col. 2, last para.). There would have been a reasonable expectation of success because Yelensky performs immunoprecipitation, and the modification would perform the immunoprecipitation using MAPcP.
Claim 40 is rejected under 35 USC 103 for being unpatentable over Yelensky et al. (“Yelensky”; US 2017/0199961 A1; effective filing date 23 Nov. 2016) in view of Duffy et al. (“Duffy”; Analytical biochemistry 262, no. 2 (1998): 122-128) and in further view of Ibe et al. (“Ibe”; Journal of biotechnology 208 (2015): 22-27).
The limitations of claim 22 are taught above by Yelensky and Duffy.
Claim 40:
Yelensky isolates HLA peptides by using immunoprecipitation with antibodies coupled to beads, where the antibody is specific for HLA class I or II [295-296]. Duffy shows in Figure 1 recombinant vector bDW449 that produces both E. coli BirA and an MBP-Raf fusion protein with a BAP joined to its N-terminus (BAP-MBP-Raf). However, Yelensky and Duffy do not teach that the BAP is linked by a cleavable linker.
Ibe discloses a single step purification of recombinant proteins using a metal ion-inducible autocleavage (MIIA) domain as a linker for affinity tag removal after protein purification (abstract). Ibe recites “target proteins MalE and mCherry were produced as MIIA-Strep fusion proteins in Escherichia coli. The target proteins could be separated from the MIIA-Strep part simply by the addition of calcium ormanganese(II) ions within minutes” (abstract).
It would have been prima facie obvious to have linked the MHC allele to the BAP of Yelensky and Duffy by introducing MIIA as a cleavable linker as taught by Ibe. Motivation is taught by Ide who teaches that affinity tags often need to be removed after purification (abstract), and MIIA is advantageous because its short reaction time and stability within a broad range of pH and temperatures (pg. 25, col. 2, last para.). There would have been a reasonable expectation of success because the cleavable linker MIIA can be inserted into fusion proteins and used for protein purification, wherein Yelensky and Duffy disclose an MHC fusion protein with a BAP used for protein purification.
Conclusion
No claims are allowed.
Claims 22-36 and 39-40 are patent eligible under 35 USC 101. As discussed in Claim Interpretation, when claim 22 is interpreted to require step ai and not steps aii – d, claim 22 recites only additional elements. Claims 27-30, 34-35 and 39-40 recite only additional elements. Thus, when claim 22, steps a – ai, and claims 27-30, 34-35 and 39-40 are viewed in combination, they recite statutory subject matter and do not recite a judicial exception. In the alternate interpretation when claim 22 requires steps aii – d, claim 22 recites additional elements in steps a and aii – c that are not well understood routine and conventional (WURC) and thus integrate the judicial exception recited in claim 22, step d. It is not WURC to contact training peptides to cells containing a recombinant MHC protein linked to an affinity acceptor peptide, wherein the cells are immunoprecipitated with an affinity molecule that binds the acceptor peptide sequence to then identify the immunoprecipitated training peptides using mass spectrometry.
Claim 41 is patent eligible under 35 USC 101 because it recites statutory subject matter and does not recite a judicial exception.
Notable, but not relied upon, prior art includes: Tareen et al. (WO 2018/005559 A1) affinity tagged recombinant MHC with immunoprecipitation and mass spectrometry analysis of MHC-peptide complex. Davis et al. (WO 2017/015064 A1) recombinant MHC proteins contain a biotin acceptor peptide which is used for isolation and purification [56] [84]. Bassani-Sternberg et al. (Current opinion in immunology 41 (2016): 9-17) reviews immunoprecipitation and mass spectrometry of antigen discovery for HLA molecules. Yang et al. (Human immunology 65, no. 7 (2004): 692-699) creates HLA construct with BSP tag for biotinylation. Cai et al. (US-8124408-B2) host cells lack endogenous MHC class I and II. Chen et al. (Advanced drug delivery reviews 65, no. 10 (2013): 1357-1369) reviews of fusion protein linkers. Barnardo et al. (EP 1385004 A1) discloses recombinant MHC containing biotinylation site where biotin enables binding to streptavidin-coated solid support [39]. Schwabe et al. (US 2009/0137472 A1) chimeric MHC protein.
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/N.A.A./Examiner, Art Unit 1687
/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685
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