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 .
Claims 7-10, 12-16, 21-35, 42, 44, and 47-50 are cancelled.
Claims 1-6, 11, 17-20, 36-41, 43, and 45-46 are pending and under examination on the merits.
Priority
This application claims benefit of US Provisional Application No. 63/432,237, filed 12/13/2022, and claims benefit of US Provisional Application No. 63/543,974, filed 10/13/2023.
IDS
The information disclosure statement (IDS) filed 07/18/2024 has been considered.
Claim Interpretation
In the art, there are various ways of referring to the same known HLA antigen. For example, HLA Protein Technologies Ince teach that HLA-C*01:02 is synonymous with the following: Cw*01:02, Cw*0102, C*0102, C0102, Cw0102, C*01, C01, Cw*01, Cw01, Cw1 (see for example, HLA-C*01:02 (HLA Protein Technologies Inc, obtained from: https://www.hlaprotein.com/hlac0102bio-c0102bio (accessed 06/04/2026)). These naming variants will be understood to be synonymous when interpreting the recited HLA variants of tables 1-6 and the prior art.
For claims 11 and 45-46, depending from claims 4 and 39, respectively, the claims are interpreted as having as little as 2 antigens from the recited tables 1-6 based upon the claim drafting.
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 2, 4-6, 11, 37-41, 43 and 45-46 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 5 and 40 recite the narrow recitation ‘10,’ and the claims also recite ‘20, 30, 40, 50 or more’ which is the broader statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
In the present instance, claims 6 and 41 recite the narrow recitation ‘5,’ and the claim also recite ‘6, 7, 8 or more’ which is the broader statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
In the present instance, claim 43 recites the narrow recitation ‘5,’ and the claim also recite ‘6, 7, 8 or more’ at various, alternative instances from different tables which is the broader statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
The MPEP provides that "where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table 'is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.' Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993)" (MPEP 2173.05(s)). Claims 2, 4-6, 11, 37-41, 43 and 45-46 all recite and reference back to tables 1-6 of the specification. This is improper and the limitations should be added into the claims for clarity of the claim scope of record.
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 (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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-6, 11, 17-20, 36-41, 43, and 45-46 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al (US 2011/0250619 A1) in view of Sypek et al (American Journal of Kidney Diseases, 2017; 71, 720-731; obtained from: https:// //www.ajkd.org/article/S0272-6386(17)31016-8/fulltext).
Regarding claims 1, 2, and 36-37, Lee et al teach a method of screening for antibodies that specifically bind a native HLA antigen, comprising the steps of:
obtaining a serum sample from a human subject, providing a first solid phase substrate (such as magnetic beads (see for example, paragraphs 0072-0073 at page 8)) having immobilized thereon said HLA antigen which has been denatured;
binding antibodies that specifically bind said denatured HLA antigens (where the antigen may be a class-I or class-II HLA-antigen (see for example, claims 3-4 and wherein single antigen HLA-immobilized beads for class I and Class II HLA antigens are taught by reference to the One Lambda beads, see exemplary paragraph 0100 at page 10) in said serum sample to said first solid-phase substrate to form an antibody/antigen complex (deemed to implicitly read upon contacting the HLA-immobilized magnetic beads with a sample); and
separating the antibody/antigen complex from the serum sample to generate a serum sample essentially free of antibodies that specifically bind said denatured HLA antigen (deemed to implicitly read on separating the HLA-antibody-HLA-immobilized magnetic bead complexes from the sample).
Lee et al teach that the following HLA-antigens were used and known in the art: (1) A0101 (recited antigen 1 at instant Table 1 at page 11 of the instant specification), (2) A2901 (recited antigen 7 at instant Table 1 at pages 11-12 of the instant specification), (3) B1501 (recited antigen 4 at instant Table 2 at page 12 of the instant specification), (4) B4402 (recited antigen 5 at instant Table 2 at page 12 of the instant specification), (5) B4601 (recited antigen 6 at instant Table 2 at page 12 of the instant specification), (6) B5701 (recited antigen 8 at instant Table 2 at page 12 of the instant specification), (7) CW0102 (recited antigen 1 at instant Table 3 at page 13 of the instant specification), (8) CW0303 (recited antigen 3 at instant Table 3 at page 13 of the instant specification), (9) CW0501 (recited antigen 6 at instant Table 3 at page 13 of the instant specification), and (10) CW1502 (recited antigen 9 at instant Table 3 at page 13 of the instant specification).
Lee et al do not teach isolation of the anti-HLA antibodies from the beads. Note that the term ‘isolating’ is not defined, but the specification seems to define the step of isolating as being a step of eluting the antibodies (see for example, paragraph 0084 at page 24 of the instant specification).
However, Sypek et al teach that describing HLA antigens as a series of antibody targets, or epitopes, rather than based on broad seroreactivity patterns or precise amino acid sequences may provide a more practical and clinically relevant system to help avoid antibody-mediated rejection, reduce sensitization, and select the most appropriate organs in the setting of pre-existing alloantibodies (see for example, the abstract). The development of microbeads coated with single HLA antigens resulted in rapid advancements in the identification and description of HLA epitopes based on antibody analysis. Sypek et al teach that El-Awar and colleagues used single-antigen beads to analyze both monoclonal anti-HLA antibodies and antibodies derived from adsorption/elution of allosera using recombinant HLA single-antigen cell lines and described 103 class I, 60 DR, and 18 DQ epitopes, which they termed TerEps (see for example, page 724). Sypek et al further teach that Table 1 shows an example of HLA and eplet matching between a kidney transplant candidate and 2 potential donors, demonstrating how eplet-based matching can provide additional detail over antigen-based matching (see pages 725-726). Sypek et al further teach that Table 2 summarizes the clinical studies examining the association between eplet mismatches and clinical outcomes in solid-organ transplantation. Sypek et al teach that an early study by Dankers et al found a strong positive correlation between the number of class I triplet mismatches and the proportion of individuals producing anti-HLA antibodies, following both failed kidney transplantation and pregnancy. Sypek et al teach that Wiebe et al have demonstrated that class II locus-specific eplet mismatches are an independent risk factor for class II de novo DSA formation. They identified thresholds for eplet mismatches that were associated with low risk for de novo DSA formation (10 for HLA-DR and 17 for HLA-DQ). Sypek et al teach that in a later study, the group showed that higher eplet mismatch and poor adherence to immunosuppressive medications acted synergistically to determine the risk for rejection and graft loss (see for example, pages 726-727).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention as claimed to discover/screen for HLA class I and II eplet mismatches in order to determine donor/recipient suitability to avoid adverse effects from transplantation. The artisan, reading Sypek et al, would have found it obvious to use single antigen beads coated in HLA-class I or HLA-class II antigens of Lee et al by contacting the beads with one or more samples in order to capture anti-HLA-bead complexes in order to elute the antibodies (by any means known in the art, such as the means taught by El-Awar et al as cited by Sypek et al) for eplet discovery/HLA mismatch analysis to prevent to select for suitable donor/recipient pairs and to decrease adverse events related to transplantation as taught by Sypek et al. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claims 3 and 38, as discussed above, Lee et al teach single antigen HLA-immobilized beads using a plurality single-antigen beads with a plurality of HLA antigens immobilized (such as the 10 antigens described above which are 10 of the HLA antigens Applicant discloses as instant Tables 1-3 of the instant specification at pages 11-13). Therefore, it would have been predictable with a reasonable expectation of success to use any known HLA-antigen or combination thereof on single antigen beads, such as the beads of Lee et al adapted as taught by Sypek et al to isolate anti-HLA antibodies from a sample for eplet analysis and HLA-compatibility analysis for pairing donors and recipients to avoid adverse events after transplantation.
Regarding claims 4-6, 39-41, and 45, as discussed above, Lee et al teach the inclusion of 10 different HLA antigens corresponding to options disclosed at instant Tables 1-6 for use on the single antigen HLA-immobilized beads.
Regarding claims 11 and 46, as discussed above, Lee et al teach single antigen HLA-immobilized beads using a plurality of HLA antigens (such as the 10 antigens described above which are 10 of the HLA antigens Applicant discloses as instant Tables 1-3 of the instant specification at pages 11-13). Therefore, not only would the predictability of using any known HLA-antigens (such as all of the antigens of instant Tables 1-6 by admission of applicant noting that all antigens were shown at ebi.ac.uk/ipd/imgt/hla/alleles/; see for example, paragraph 0038 at page 11 of the instant specification) on single antigen beads, such as the beads of Lee et al adapted as taught by Sypek et al to isolate anti-HLA antibodies from a sample for eplet analysis and HLA-compatibility analysis for pairing donors and recipients to avoid adverse events after transplantation. It is clear that any art-known HLA antigen could be readily and predictably immobilized on a bead according to Lee et al and Sypek et al. The inclusion/exclusion of given HLA antigens for the beads to be used would appear to be a mere matter of choice yielding no more that predictable results, where the particular combination of antigens is simply a variable to be chosen by the artisan for devising an optimized panel of antigens to screen for donor/recipient HLA-compatibility via eplet matching/mismatching. Therefore, because the beads and their use are known in the art and because the HLA antigens of Tables 1-6 are known in the art, the claim limitations are deemed to be obvious over the Lee et al in view of Sypek where Applicant admits the HLA antigens of Tables 1-6 are known in the art both by explicit reference to ebi.ac.uk/ipd/imgt/hla/alleles/ and by the use of antigen naming which, had the antigens not ben previously known, would be deemed to fail to meet various provision under 35 USC §112 such as failure to provide definite written description for the claimed antigens.
Regarding claim 43, as discussed above, Lee et al teach that the following HLA-antigens were used and known in the art: (1) A0101 (recited antigen 1 at instant Table 1 at page 11 of the instant specification), (2) A2901 (recited antigen 7 at instant Table 1 at pages 11-12 of the instant specification), (3) B1501 (recited antigen 4 at instant Table 2 at page 12 of the instant specification), (4) B4402 (recited antigen 5 at instant Table 2 at page 12 of the instant specification), (5) B4601 (recited antigen 6 at instant Table 2 at page 12 of the instant specification), (6) B5701 (recited antigen 8 at instant Table 2 at page 12 of the instant specification), (7) CW0102 (recited antigen 1 at instant Table 3 at page 13 of the instant specification), (8) CW0303 (recited antigen 3 at instant Table 3 at page 13 of the instant specification), (9) CW0501 (recited antigen 6 at instant Table 3 at page 13 of the instant specification), and (10) CW1502 (recited antigen 9 at instant Table 3 at page 13 of the instant specification). Antigens B1501, B4402, B4601, and B5701 represent 4 of the antigens noted at instant Table 2 at page 12 of the instant specification.
Lee at al do not teach a fifth antigen from table 2.
However, Sypek et al teach that the B0702 antigen (antigen 1 at table 2 of page 12 of the instant specification) was known in the art for eplet and HLA pair matching between donors and recipients.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. Not only would the predictability of using any known HLA-antigens (such as all of the antigens of instant Tables 1-6 by admission of applicant noting that all antigens were shown at ebi.ac.uk/ipd/imgt/hla/alleles/; see for example, paragraph 0038 at page 11 of the instant specification) on single antigen beads, such as the beads of Lee et al adapted as taught by Sypek et al to isolate anti-HLA antibodies from a sample for eplet analysis and HLA-compatibility analysis for pairing donors and recipients to avoid adverse events after transplantation. It is clear that any art-known HLA antigen could be readily and predictably immobilized on a bead according to Lee et al and Sypek et al. The inclusion/exclusion of given HLA antigens for the beads to be used would appear to be a mere matter of choice yielding no more that predictable results, where the particular combination of antigens is simply a variable to be chosen by the artisan for devising an optimized panel of antigens to screen for donor/recipient HLA-compatibility via eplet matching/mismatching. Therefore, because the beads and their use are known in the art and because the HLA antigens of Tables 1-6 are known in the art, the claim limitations are deemed to be obvious over the Lee et al in view of Sypek where Applicant admits the HLA antigens of Tables 1-6 are known in the art both by explicit reference to ebi.ac.uk/ipd/imgt/hla/alleles/ and by the use of antigen naming which, had the antigens not ben previously known, would be deemed to fail to meet various provision under 35 USC §112 such as failure to provide definite written description for the claimed antigens.
Regarding claims 17-18, as discussed above, claim 1 of Lee et al recites contacting HLA-immobilized beads with a serum sample, which is a blood sample (see also, exemplary paragraph 0077 of Lee et al).
Regarding claim 19, the claim appears to recite a result of practicing the method of claim 1, not an active step. Therefore, practicing the method of claim 1 (with the implied limitation that the sample contacted with the beads from which anti-HLA antibodies are eluted is from the potential recipient), makes obvious the instant limitation. Here, Lee et al teach that the sample with which the beads are contacted so as to form a HLA-immobilized bead-anti-HLA antibody complexes may be from the potential recipient (see for example, paragraph 0077) where Sypek et al teach that HLA antigen mismatches are associated with an increased risk for developing de novo anti-HLA donor-specific antibodies (DSAs), which are most commonly anti–HLA-DQ, and are in turn associated with poorer graft survival and increased sensitization, which would motivate the artisan to use the prior art method of Lee et al and Sypek et al to screen for DSA by contacting the HLA-immobilized beads with a recipient sample to capture and elute DSA for eplet analysis, matching, such as against the donor’s HLA type (such as with free HLA matching software such as HLAMatchmaker) (see for example, column 2 of page 722 and pages 725-726).
Regarding claim 20, note that no closed and clear definition is provided for the term ‘epitope analysis’. However, the term seems to be used synonymously with eplet identification (see exemplary paragraphs 0015 at page 4, 0059 at page 17, and 0068 at page 19 of the instant specification). As discussed above, Sypek et al teach that El-Awar et al used single-antigen beads to analyze both monoclonal anti-HLA antibodies and antibodies derived from adsorption/elution of allosera using recombinant HLA single-antigen cell lines and described 103 class I, 60 DR, and 18 DQ epitopes, which they termed TerEps (see for example, column 1 of page 724). Sypek et al demonstrate and teach eplet matching of a kidney transplant candidate and 2 potential donors, demonstrating how eplet-based matching can provide additional detail over antigen-based matching (see for example, pages 725-726). Sypek et al additionally teach that testing for allele-specific anti-HLA antibodies using solid-phase assays (Fig 3) is now widely available, with its role in clinical transplantation continuing to evolve. Many jurisdictions use the population frequencies of HLA typing to determine calculated panel-reactive anti bodies based on the specificity of a potential recipient’s anti-HLA antibody profile. This number represents the percentage of the donor pool with whom the recipient is predicted to have a positive cross-match63 and is increasingly being used in organ allocation algorithms (see for example, page 722). This teaching is deemed to read upon cross-matching as no closed definition is provided in the specification. The artisan would have found it obvious to use the beads of Lee et al according to the methods of Sypek et al to enhance eplet/HLA matching to better match donors and recipients to reduce the risk of adverse events post-transplantation.
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 1-6, 11, 17-20, 36-41, 43, and 45-46 are rejected or provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-7 of U.S. Patent No. 8628932 (reference A);
claims 1-14 of U.S. Patent No. 12332243 (reference B);
claims 1- 13 of U.S. Patent No. 7972804 (reference C);
claims 1-15 of U.S. Patent No. 6514714 (reference D);
claims 1-2 of U.S. Patent No. 5948627 (reference E);
claims 1-22 of U.S. Patent No. 8927290 (reference F); and/or
claims 1-20 of copending Application No. 19/316,393 (‘393) (rejections over ‘393 are provisional),
in view of Lee et al (US 2011/0250619 A1) in view of Sypek et al (American Journal of Kidney Diseases, 2017; 71, 720-731; obtained from: https:// //www.ajkd.org/article/S0272-6386(17)31016-8/fulltext).
Regarding claims 1-6, 11, 1720, 36-41, 43, and 46-46, the above enumerated claims of references A-F and ‘393 are directed to methods using and/or compositions comprising HLA antigens immobilized on a substrate/support, said substrate/support encompassing a bead.
The above enumerated claims of references A-F and ‘393 do not claim the particular HLA antigens of Tables 1-6 and/or the use of the beads for isolating antibodies from a sample,
However, this is obvious in view Lee et al and Sypek et al, as discussed below.
Regarding claims 1, 2, and 36-37, Lee et al teach a method of screening for antibodies that specifically bind a native HLA antigen, comprising the steps of:
obtaining a serum sample from a human subject, providing a first solid phase substrate (such as magnetic beads (see for example, paragraphs 0072-0073 at page 8)) having immobilized thereon said HLA antigen which has been denatured;
binding antibodies that specifically bind said denatured HLA antigens (where the antigen may be a class-I or class-II HLA-antigen (see for example, claims 3-4 and wherein single antigen HLA-immobilized beads for class I and Class II HLA antigens are taught by reference to the One Lambda beads, see exemplary paragraph 0100 at page 10) in said serum sample to said first solid-phase substrate to form an antibody/antigen complex (deemed to implicitly read upon contacting the HLA-immobilized magnetic beads with a sample); and
separating the antibody/antigen complex from the serum sample to generate a serum sample essentially free of antibodies that specifically bind said denatured HLA antigen (deemed to implicitly read on separating the HLA-antibody-HLA-immobilized magnetic bead complexes from the sample).
Lee et al teach that the following HLA-antigens were used and known in the art: (1) A0101 (recited antigen 1 at instant Table 1 at page 11 of the instant specification), (2) A2901 (recited antigen 7 at instant Table 1 at pages 11-12 of the instant specification), (3) B1501 (recited antigen 4 at instant Table 2 at page 12 of the instant specification), (4) B4402 (recited antigen 5 at instant Table 2 at page 12 of the instant specification), (5) B4601 (recited antigen 6 at instant Table 2 at page 12 of the instant specification), (6) B5701 (recited antigen 8 at instant Table 2 at page 12 of the instant specification), (7) CW0102 (recited antigen 1 at instant Table 3 at page 13 of the instant specification), (8) CW0303 (recited antigen 3 at instant Table 3 at page 13 of the instant specification), (9) CW0501 (recited antigen 6 at instant Table 3 at page 13 of the instant specification), and (10) CW1502 (recited antigen 9 at instant Table 3 at page 13 of the instant specification).
Lee et al do not teach isolation of the anti-HLA antibodies from the beads. Note that the term ‘isolating’ is not defined, but the specification seems to define the step of isolating as being a step of eluting the antibodies (see for example, paragraph 0084 at page 24 of the instant specification).
However, Sypek et al teach that describing HLA antigens as a series of antibody targets, or epitopes, rather than based on broad seroreactivity patterns or precise amino acid sequences may provide a more practical and clinically relevant system to help avoid antibody-mediated rejection, reduce sensitization, and select the most appropriate organs in the setting of pre-existing alloantibodies (see for example, the abstract). The development of microbeads coated with single HLA antigens resulted in rapid advancements in the identification and description of HLA epitopes based on antibody analysis. Sypek et al teach that El-Awar and colleagues used single-antigen beads to analyze both monoclonal anti-HLA antibodies and antibodies derived from adsorption/elution of allosera using recombinant HLA single-antigen cell lines and described 103 class I, 60 DR, and 18 DQ epitopes, which they termed TerEps (see for example, page 724). Sypek et al further teach that Table 1 shows an example of HLA and eplet matching between a kidney transplant candidate and 2 potential donors, demonstrating how eplet-based matching can provide additional detail over antigen-based matching (see pages 725-726). Sypek et al further teach that Table 2 summarizes the clinical studies examining the association between eplet mismatches and clinical outcomes in solid-organ transplantation. Sypek et al teach that an early study by Dankers et al found a strong positive correlation between the number of class I triplet mismatches and the proportion of individuals producing anti-HLA antibodies, following both failed kidney transplantation and pregnancy. Sypek et al teach that Wiebe et al have demonstrated that class II locus-specific eplet mismatches are an independent risk factor for class II de novo DSA formation. They identified thresholds for eplet mismatches that were associated with low risk for de novo DSA formation (10 for HLA-DR and 17 for HLA-DQ). Sypek et al teach that in a later study, the group showed that higher eplet mismatch and poor adherence to immunosuppressive medications acted synergistically to determine the risk for rejection and graft loss (see for example, pages 726-727).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention as claimed to discover/screen for HLA class I and II eplet mismatches in order to determine donor/recipient suitability to avoid adverse effects from transplantation. The artisan, reading Sypek et al, would have found it obvious to use single antigen beads coated in HLA-class I or HLA-class II antigens of Lee et al by contacting the beads with one or more samples in order to capture anti-HLA-bead complexes in order to elute the antibodies (by any means known in the art, such as the means taught by El-Awar et al as cited by Sypek et al) for eplet discovery/HLA mismatch analysis to prevent to select for suitable donor/recipient pairs and to decrease adverse events related to transplantation as taught by Sypek et al. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claims 3 and 38, as discussed above, Lee et al teach single antigen HLA-immobilized beads using a plurality single-antigen beads with a plurality of HLA antigens immobilized (such as the 10 antigens described above which are 10 of the HLA antigens Applicant discloses as instant Tables 1-3 of the instant specification at pages 11-13). Therefore, it would have been predictable with a reasonable expectation of success to use any known HLA-antigen or combination thereof on single antigen beads, such as the beads of Lee et al adapted as taught by Sypek et al to isolate anti-HLA antibodies from a sample for eplet analysis and HLA-compatibility analysis for pairing donors and recipients to avoid adverse events after transplantation.
Regarding claims 4-6, 39-41, and 45, as discussed above, Lee et al teach the inclusion of 10 different HLA antigens corresponding to options disclosed at instant Tables 1-6 for use on the single antigen HLA-immobilized beads.
Regarding claims 11 and 46, as discussed above, Lee et al teach single antigen HLA-immobilized beads using a plurality of HLA antigens (such as the 10 antigens described above which are 10 of the HLA antigens Applicant discloses as instant Tables 1-3 of the instant specification at pages 11-13). Therefore, not only would the predictability of using any known HLA-antigens (such as all of the antigens of instant Tables 1-6 by admission of applicant noting that all antigens were shown at ebi.ac.uk/ipd/imgt/hla/alleles/; see for example, paragraph 0038 at page 11 of the instant specification) on single antigen beads, such as the beads of Lee et al adapted as taught by Sypek et al to isolate anti-HLA antibodies from a sample for eplet analysis and HLA-compatibility analysis for pairing donors and recipients to avoid adverse events after transplantation. It is clear that any art-known HLA antigen could be readily and predictably immobilized on a bead according to Lee et al and Sypek et al. The inclusion/exclusion of given HLA antigens for the beads to be used would appear to be a mere matter of choice yielding no more that predictable results, where the particular combination of antigens is simply a variable to be chosen by the artisan for devising an optimized panel of antigens to screen for donor/recipient HLA-compatibility via eplet matching/mismatching. Therefore, because the beads and their use are known in the art and because the HLA antigens of Tables 1-6 are known in the art, the claim limitations are deemed to be obvious over the Lee et al in view of Sypek where Applicant admits the HLA antigens of Tables 1-6 are known in the art both by explicit reference to ebi.ac.uk/ipd/imgt/hla/alleles/ and by the use of antigen naming which, had the antigens not ben previously known, would be deemed to fail to meet various provision under 35 USC §112 such as failure to provide definite written description for the claimed antigens.
Regarding claim 43, as discussed above, Lee et al teach that the following HLA-antigens were used and known in the art: (1) A0101 (recited antigen 1 at instant Table 1 at page 11 of the instant specification), (2) A2901 (recited antigen 7 at instant Table 1 at pages 11-12 of the instant specification), (3) B1501 (recited antigen 4 at instant Table 2 at page 12 of the instant specification), (4) B4402 (recited antigen 5 at instant Table 2 at page 12 of the instant specification), (5) B4601 (recited antigen 6 at instant Table 2 at page 12 of the instant specification), (6) B5701 (recited antigen 8 at instant Table 2 at page 12 of the instant specification), (7) CW0102 (recited antigen 1 at instant Table 3 at page 13 of the instant specification), (8) CW0303 (recited antigen 3 at instant Table 3 at page 13 of the instant specification), (9) CW0501 (recited antigen 6 at instant Table 3 at page 13 of the instant specification), and (10) CW1502 (recited antigen 9 at instant Table 3 at page 13 of the instant specification). Antigens B1501, B4402, B4601, and B5701 represent 4 of the antigens noted at instant Table 2 at page 12 of the instant specification.
Lee at al do not teach a fifth antigen from table 2.
However, Sypek et al teach that the B0702 antigen (antigen 1 at table 2 of page 12 of the instant specification) was known in the art for eplet and HLA pair matching between donors and recipients.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. Not only would the predictability of using any known HLA-antigens (such as all of the antigens of instant Tables 1-6 by admission of applicant noting that all antigens were shown at ebi.ac.uk/ipd/imgt/hla/alleles/; see for example, paragraph 0038 at page 11 of the instant specification) on single antigen beads, such as the beads of Lee et al adapted as taught by Sypek et al to isolate anti-HLA antibodies from a sample for eplet analysis and HLA-compatibility analysis for pairing donors and recipients to avoid adverse events after transplantation. It is clear that any art-known HLA antigen could be readily and predictably immobilized on a bead according to Lee et al and Sypek et al. The inclusion/exclusion of given HLA antigens for the beads to be used would appear to be a mere matter of choice yielding no more that predictable results, where the particular combination of antigens is simply a variable to be chosen by the artisan for devising an optimized panel of antigens to screen for donor/recipient HLA-compatibility via eplet matching/mismatching. Therefore, because the beads and their use are known in the art and because the HLA antigens of Tables 1-6 are known in the art, the claim limitations are deemed to be obvious over the Lee et al in view of Sypek where Applicant admits the HLA antigens of Tables 1-6 are known in the art both by explicit reference to ebi.ac.uk/ipd/imgt/hla/alleles/ and by the use of antigen naming which, had the antigens not ben previously known, would be deemed to fail to meet various provision under 35 USC §112 such as failure to provide definite written description for the claimed antigens.
Regarding claims 17-18, as discussed above, claim 1 of Lee et al recites contacting HLA-immobilized beads with a serum sample, which is a blood sample (see also, exemplary paragraph 0077 of Lee et al).
Regarding claim 19, the claim appears to recite a result of practicing the method of claim 1, not an active step. Therefore, practicing the method of claim 1 (with the implied limitation that the sample contacted with the beads from which anti-HLA antibodies are eluted is from the potential recipient), makes obvious the instant limitation. Here, Lee et al teach that the sample with which the beads are contacted so as to form a HLA-immobilized bead-anti-HLA antibody complexes may be from the potential recipient (see for example, paragraph 0077) where Sypek et al teach that HLA antigen mismatches are associated with an increased risk for developing de novo anti-HLA donor-specific antibodies (DSAs), which are most commonly anti–HLA-DQ, and are in turn associated with poorer graft survival and increased sensitization, which would motivate the artisan to use the prior art method of Lee et al and Sypek et al to screen for DSA by contacting the HLA-immobilized beads with a recipient sample to capture and elute DSA for eplet analysis, matching, such as against the donor’s HLA type (such as with free HLA matching software such as HLAMatchmaker) (see for example, column 2 of page 722 and pages 725-726).
Regarding claim 20, note that no closed and clear definition is provided for the term ‘epitope analysis’. However, the term seems to be used synonymously with eplet identification (see exemplary paragraphs 0015 at page 4, 0059 at page 17, and 0068 at page 19 of the instant specification). As discussed above, Sypek et al teach that El-Awar et al used single-antigen beads to analyze both monoclonal anti-HLA antibodies and antibodies derived from adsorption/elution of allosera using recombinant HLA single-antigen cell lines and described 103 class I, 60 DR, and 18 DQ epitopes, which they termed TerEps (see for example, column 1 of page 724). Sypek et al demonstrate and teach eplet matching of a kidney transplant candidate and 2 potential donors, demonstrating how eplet-based matching can provide additional detail over antigen-based matching (see for example, pages 725-726). Sypek et al additionally teach that testing for allele-specific anti-HLA antibodies using solid-phase assays (Fig 3) is now widely available, with its role in clinical transplantation continuing to evolve. Many jurisdictions use the population frequencies of HLA typing to determine calculated panel-reactive anti bodies based on the specificity of a potential recipient’s anti-HLA antibody profile. This number represents the percentage of the donor pool with whom the recipient is predicted to have a positive cross-match63 and is increasingly being used in organ allocation algorithms (see for example, page 722). This teaching is deemed to read upon cross-matching as no closed definition is provided in the specification. The artisan would have found it obvious to use the beads of Lee et al according to the methods of Sypek et al to enhance eplet/HLA matching to better match donors and recipients to reduce the risk of adverse events post-transplantation.
Where references A-F and/or ‘393 claim a scope encompassing HLA-immobilized beads, the artisan would have found it obvious to modify the HLA-Immobilized beads of references A-F and/or ‘393 according to Lee et al and Sypek et al in order to optimized the HLA-immobilized beads used in according to Lee et al and Sypek et al to better pair donors to recipients and to reduce the risk of adverse events post-transplantation.
The artisan would have had a reasonable expectation of success prior to the instant effective filing date based on the cumulative disclosures of references A-F and/or ‘393 in view of Lee et al and Sypek et al.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Fadeyi et al (Transfusion. 2008 Jun;48(6):1174-9. doi: 10.1111/j.1537-2995.2008.01684.x. Epub 2008 Apr 15) teach that passive infusion of HLA antibodies has been implicated in transfusion reactions. A rapid, inexpensive method of screening blood donors for HLA antibodies might reduce the incidence of reactions (see for example, the abstract at page 1). One such method uses up to 100 different color-coded microbeads and a modified flow cytometer or flow analyzer. This platform also can be used for high-throughput testing of antibodies to HLA Class I and II antigens. When the microbead-flow analyzer is used for HLA antibody testing, the color-coded microbeads are coated with HLA antigens and after serum or plasma is incubated with the antigen coated microbeads, fluorochrome-labeled antihuman IgG is added and a flow analyzer is used to determine the color-code of the reactive beads and hence the specific antigen(s) to which the antibody is reactive. If the microbeads are coated with antigens from individual cells, the assay can be used to determine the percentage of panel reactive antibodies (PRA) and antibody specificities can be identified using microbeads coated with single HLA antigens. The microbead-flow analyzer assay may be useful for screening blood donors for antibodies to HLA antigens (see for example, page 2). Whole blood samples were collected and serum was separated from the whole blood. The serum samples were analyzed for the presence of IgG antibodies to HLA Class I and Class II antigens where the analysis included testing samples with color-coded microbeads coated with HLA antigen (LABScreen, One Lambda, Inc. Canoga CA) and analysis with a flow analyzer (LABScan 100 flow analyzer, One Lambda). All samples were first tested against microbeads coated with a mixture of HLA Class I and Class II antigens (LABScreen Mixed, One Lambda). Samples reactive in the mixed antigen microbead assay were then tested with microbeads coated with HLA antigens from individual cells (LABScreen PRA, One Lambda) (See for example, page 2). In the limited number of samples tested in this study there was a very good correlation between the results of PRA assay and the microbead-flow analyzer single antigen assay suggesting that there were be less false positive reactions with the PRA or single antigen-bead assays than with the mixed antigen assay. The prevalence of both Class I and II antibodies detected in the microbead-flow analyzer assay was much greater than in the ELISA assay. Since the results of testing reactive samples in the microbead-flow analyzer assay were confirmed with a PRA assay and sometimes single antigen assay, these likely represent true positive results. (see for example, the discussion section at page 5).
WO2011003598A2 and WO2012122372A2 are deemed relevant.
Godat et al (High-Capacity and High-PurityAntibody Purification Using Magnetic Beads Promega Notes; obtained from: https://www.promega.com/resources/pubhub/high-capacity-and-high-purity-antibody-purification/ (pub. 2012)), El-Awar (Clin. Transpl.
2007:175-94), El-Awar (J. Immunol. Res. Vol 2017, Article ID 3406230, 16 pages;
https:/ /doi.org/ 10.1155/2017 /3406230), Clerkin et al (Transplantation Direct 3(11):p e218, November 2017. | DOI: 10.1097/TXD.0000000000000734), Billen et al (Tissue Antigens 71, 507-513; doi: 10.1111/j.1399-0039.2008.01032.x (2008)), Argani et al (Experimental and Clinical Transplantation : Official Journal of the Middle East Society for Organ Transplantation, 01 Jan 2019, 17(Suppl 1):38-42DOI:10.6002/ect.MESOT2018.L41), Bezstarosti et al (Front. Immunol. 12:800946.; doi: 10.3389/fimmu.2021.800946 (pub. Jan 2022)), and Biocompare (Labscreen Single Antigen Beads from One Lambda (2013); obtained from: https://www.biocompare.com/Product-Reviews/136400-LabScreen-Single-Antigen-Beads-from-One-Lambda/), all of the references cited on the 07/18/2024 IDS (and refences cited on the ISA search report cited therein) are deemed relevant to the claimed subject matter.
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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