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 currently pending and are herein under examination.
Claims 1-21 are rejected.
Claims 1-21 are objected.
Priority
The instant application claims domestic benefit as a 371 to International Application PCT/US2020/060461 filed November 13, 2020, which claims domestic benefit to U.S. Provisional Patent Application No. 62/934,663 filed November 13, 2019. The claims to domestic benefit are acknowledged for claims 1-21. As such, the effective filing date for claims 1-21 is November 13, 2019.
Information Disclosure Statement
The IDSs filed 05/10/2022, 11/29/2022 and 12/20/2023 follow the provisions of 37 CFR 1.97 and has been considered in full. A signed copy of the list of references cited from these IDSs is included with this Office Action.
Drawings
The drawings filed 05/10/2022 are objected to because they do not comply with 37 CFR 1.84(u)(1), which requires figures to be numbered in consecutive Arabic numerals. The drawing titled “Supplemental FIG. 1” should be amended to recite “FIG. 6”.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. The hyperlinks are on pg. 21, line 29; pg. 22, line 1; and pg. 25, line 29. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The specification is also objected to because “Supplemental Figure 1” in the Brief Description of the Drawings should be changed to “Figure 6”, so that the amendment to the drawings discussed above in the Drawings section is reflected in the specification.
Claim Objections
Claims 1-21 are objected to because of the following informalities:
Claim 1, line 3, recites the phrase “receiving as inputs,” which should be “receiving as inputs” because the comma appears to not serve a purpose in the clause.
Claim 2, lines 1-2, recites the phrase “physical-crossmatch-outcome- data derived model” which should be “physical-crossmatch-outcome-data-derived model”.
Claim 2, line 1, recites the phrase “The method of claim 1 wherein” which should be “The method of claim 1, wherein”.
Claim 3, line 1, recites the phrase “The method of claim 2 wherein” which should be “The method of claim 2, wherein”.
Claim 4, line 1, recites the phrase “The method of claim 1 wherein” which should be “The method of claim 1, wherein”.
Claim 5, line 1, recites the phrase “The method of claim 4 wherein” which should be “The method of claim 4, wherein”.
Claim 6, line 1, recites the phrase “The method of claim 1 comprising:” which should be “The method of claim 1, further comprising:”.
Claim 7, line 1, recites the phrase “The method of claim 6 comprising” which should be “The method of claim 6, further comprising”.
Claim 8, line 4, contains irregular spacing between the words which should be fixed.
Claim 8, line 6, recites the phrase “receiving as inputs,” which should be “receiving as inputs” because the comma appears to not serve a purpose in the clause.
Claim 8, lines 9-10, recites the phrase “a physical-crossmatch-outcome-data-derived model” which should be changed to “the physical-crossmatch-outcome-data-derived model” to properly refer to the same phrase in line 4.
Claim 9, line 1, recites the phrase “The system of claim 8 wherein” which should be “The system of claim 8, wherein”.
Claim 9, lines 1-2, recites the phrase “physical-crossmatch-outcome- data derived model” which should be “physical-crossmatch-outcome-data-derived model”.
Claim 10, line 1, recites the phrase “The system of claim 9 wherein” which should be “The system of claim 9, wherein”.
Claim 11, line 1, recites the phrase “The system of claim 8 wherein” which should be “The system of claim 8, wherein”.
Claim 12, line 1, recites the phrase “The system of claim 11wherein” which should recite “The system of claim 11, wherein”.
Claim 13, line 1, recites the phrase “The system of claim 8 comprising” which should recite “The system of claim 8, further comprising”.
Claim 14, line 1, recites the phrase “The system of claim 13 wherein” which should be “The system of claim 13, wherein”.
Claim 15, line 4, recites the phrase “receiving as inputs,” which should be “receiving as inputs” because the comma appears to not serve a purpose in the clause.
Claim 16, line 1, recites the phrase “The non-transitory computer readable medium of claim 15 wherein” which should be “The non-transitory computer readable medium of claim 15, wherein”.
Claim 16, line 2, recites the phrase “physical-crossmatch-outcome- data derived model” which should be “physical-crossmatch-outcome-data-derived model”.
Claim 17, line 1, recites the phrase “The non-transitory computer readable medium of claim 16 wherein” which should be “The non-transitory computer readable medium of claim 16, wherein”.
Claim 18, line 1, recites the phrase “The non-transitory computer readable medium of claim 15 wherein” which should be “The non-transitory computer readable medium of claim 15, wherein”.
Claim 18, line 2, contains irregular spacing between the words which should be fixed.
Claim 19, line 1, recites the phrase “The non-transitory computer readable medium of claim 18 wherein” which should be “The non-transitory computer readable medium of claim 18, wherein”.
Claim 20, line 1, recites the phrase “The non-transitory computer readable medium of claim 15 comprising:” which should recite “The non-transitory computer readable medium of claim 15, wherein the executable instructions further control the computer to perform:”. This is to clarify that the claim further limits the executable instructions of the computer readable medium.
Claim 21, line 1, recites the phrase “The non-transitory computer readable medium of claim 20 comprising:” which should recite “The non-transitory computer readable medium of claim 20, wherein the executable instructions further control the computer to perform”. This is to clarify that the claim further limits the executable instructions of the computer readable medium.
Appropriate correction is required.
Claim interpretation
Claim 13 recites the phrase “The system of claim 8 comprising an HLA data pre-processor for: deriving … removing … and providing …”. The broadest reasonable interpretation of this phrase includes the steps of deriving, removing, and providing being an intended use of the HLA data pre-processor because of the word “for”. MPEP 2114.II recites “[A]pparatus claims cover what a device is, not what a device does.” However, in the interest of compact prosecution, claim 13 is being examined as if it requires performing the steps of deriving, removing, and providing.
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 4-5, 8-14 and 18-19 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 4, 11 and 18 recite the phrase “where weights applied to the HLA DSA MFI values are derived by selecting values for the weights that …”, which renders these claims indefinite. It is unclear if this phrase requires an active step of selecting values for the weights, or if it is a product-by-process limitation that defines how the product of “weights” were derived using the previously performed process of “selecting values for the weight that …”. If Applicant intends this phrase to recite an active step, it is suggested to amend claims 4, 11 and 18 such that deriving weights by selecting values for the weights is an active step. In the interest of compact prosecution, claims 4, 11 and 18 are being interpreted as if they required an active step of selecting values for the weights.
Claims 5, 12 and 19 are also rejected because they depend on claims 4, 11 and 18, respectively, which are rejected above, and because they do not resolve the issue of indefiniteness.
Claim 8 is rejected for indefiniteness because it is unclear which limitations are required to be performed by the system and which limitations are an intended use of the model. MPEP 2114.II recites “[A]pparatus claims cover what a device is, not what a device does.” Specifically, claim 8 recites “A system … the system comprising: a computing platform including at least one processor; a physical-crossmatch-outcome-data-derived model implemented by the at least one processor for: receiving … generating … and using …”. The broadest reasonable interpretation of claim 8 is a system comprising a computing platform with at least one processor and a model, wherein the model is implemented by the processor for receiving, generating, and using. The word “for” indicates that receiving, generating, and using are an intended use of the model by the processor. Thus, it is unclear if receiving, generating, and using are required to be performed by the system. To overcome this rejection, it is suggested to amend the phrase “a physical-crossmatch-outcome-data-derived model implemented by the at least one processor for: receiving … generating … and using …” to “wherein the at least one processor is configured to implement a physical-crossmatch-outcome-data-derived model by: receiving … generating … and using …”. This amendment will clarify that the processor is configured to perform the steps of the model. In the interest of compact prosecution, claim 8 is being interpreted as if the processor is configured to perform the steps of the model.
Claims 9-14 are also rejected because they depend on claim 8, which is rejected above, and because they do not resolve the issue of indefiniteness.
Claims 10 and 12 are also rejected for indefiniteness for the same reasons applied above to claim 8 because it is unclear which limitations are required to be performed by the system and which limitations are an intended use of the model. To overcome this rejection, it is suggested to clarify that the at least one processor is configured to implement the model by performing the limitations in claims 10 and 12. In the interest of compact prosecution, claims 10 and 12 are being interpreted as if the processor is configured to perform the limitations in these claims.
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 1-21 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea and a natural phenomenon without significantly more.
Step 2A, Prong 1:
In accordance with MPEP § 2106, claims found to recite statutory subject matter (Step 1: YES) are then analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature or natural phenomena (Step 2A, Prong 1). In the instant application, claims 1-7 recite a method, claims 8-14 recite a system, and claims 15-21 recite a product. The instant claims recite the following limitations that equate to one or more categories of judicial exception:
Claims 1, 8 and 15 recite “receiving as inputs, human leukocyte antigen (HLA) antibody mean fluorescence intensity (MFI) data of a prospective tissue recipient and HLA typing data of a tissue donor; generating, based on the inputs and a physical-crossmatch- outcome-data-derived model, a predicted virtual crossmatch outcome for the prospective tissue recipient; and using the predicted virtual crossmatch outcome to inform a transplant decision for the prospective tissue recipient.”
Claims 2, 9 and 16 recite “wherein the physical-crossmatch-outcome- data derived model comprises an optimal threshold model wherein HLA donor specific antibody (DSA) MFI values of the prospective tissue recipient are summed and compared to a threshold determined empirically from physical crossmatch outcomes of a plurality of patients.”
Claims 3, 10 and 17 recite “wherein using the predicted virtual crossmatch outcome to inform a transplant decision includes determining not to perform the transplant if the sum of the HLA DSA MFI values is greater than the threshold.”
Claims 4, 11 and 18 recite “wherein the physical-crossmatch-outcome-data- derived model comprises a weighted sum of HLA donor specific antibody (DSA) MFI values, where weights applied to the HLA DSA MFI values are derived by selecting values for the weights that minimize a function of predicted median channel shifts determined for the HLA DSA MFI values and true physical crossmatch median channel shifts determined from HLA DSA MFI values for a set of patients.”
Claims 5, 12 and 19 recite “wherein using the predicted virtual crossmatch outcome to inform a transplant decision includes determining not to perform the transplant if a median channel shift calculated for a patient exceeds a median channel shift cutoff.”
Claims 6, 13 and 20 recite “deriving a list of recipient and donor eplet data from the recipient HLA MFI data, recipient HLA typing data, and the donor HLA typing data; removing, from the list, eplets that are common to the recipient and donor eplet data; and providing the eplets remaining in the list as the inputs to the physical-crossmatch-outcome-data-derived model.”
Claims 7, 14 and 21 recite “removing unverified eplets from the list prior to providing the eplets as the inputs to the physical- crossmatch-outcome-data-derived model.”
Claim 8 recites “… a physical-crossmatch-outcome-data-derived model …”
Limitations reciting a mental process.
Above cited claims 1-21 are recited at such a high level of generality that they equate to a mental process because they are similar to the concepts 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 concepts that can be practically performed in the human mind. The paragraphs below discuss the limitations in these claims that recite a mental process under their broadest reasonable interpretation (BRI).
The BRI of claims 1, 8 and 15 of receiving recipient HLA MFI values and donor HLA typing data to generate a predicted virtual crossmatch (VXM) using a physical-crossmatch-outcome-data-driven model includes acquiring the HLA MFI data and HLA typing data from a database and comparing the HLA MFI data to the HLA typing data. The comparison includes determining donor specific antibodies (DSA) by finding HLA molecules that were reactive in the HLA MFI data that are also present the donor’s HLA typing. This comparison can indicate a high risk of rejection when a DSA MFI value is above a threshold (i.e., positive). A human can then use the VXM predictions to determine whether or not to perform the transplant.
The BRI of claims 2-3, 9-10 and 16-17 includes summing HLA DSA MFI values and comparing them to a predetermined threshold, wherein a human decides not to perform the transplant when the sum of the HLA DSA MFI values is greater than the predetermined threshold.
The BRI of claims 4-5, 11-12 and 18-19 includes using a least-squares model as described on specification pg. 9, line 21 – pg. 10, line 10. A human is capable of performing the calculations of a least-squares on pen and paper as well as selecting values for weights, wherein a human decides not to perform the transplant when a patient’s median channel shift exceeds a median channel shift cutoff.
The BRI of claims 6-7, 13-14 and 20-21 includes analyzing data to generate a list, eliminating data from the list, and using data within the list as input into the crossmatch model. A human is capable of collecting, organizing, and manipulating data as well as inputting data into a model.
Limitations reciting a mathematical concept.
Above cited claims 1-2, 4, 8-9, 11, 15-16 and 18 equate to a mathematical concept because these claims are similar to the concepts of organizing and manipulating information through mathematical correlations in Digitech Image Techs., LLC v Electronics for Imaging, Inc. (758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)), which the courts have identified as mathematical concepts. The paragraphs below discuss the limitations in these claims that recite a mathematical concept under their broadest reasonable interpretation (BRI).
The BRI of claims 1, 8 and 15 includes performing the calculations of a least squares fitting method as recited on specification pg. 9, line 21 – pg. 10, line 10. This interpretation is the same for claims 4, 11 and 18. The BRI of claims 4, 11 and 18 includes further calculations because they recite summing and weighting numerical values.
The BRI of claims 2, 9 and 16 includes performing calculations because they recite summing numerical values.
Limitations reciting a natural phenomenon.
Above cited claims 1-21 equate to a natural phenomenon because they are similar to the concept of a correlation between the presence of myeloperoxidase in a bodily sample (such as blood or plasma) and cardiovascular disease risk, Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017), which the courts have established as a natural phenomenon. The BRI of claims 1-21 includes using recipient HLA MFI values, donor HLA typing data, and recipient HLA typing data to determine whether a transplant should be performed based upon a risk of rejection.
As such, claims 1-21 recite an abstract idea and a natural phenomenon (Step 2A, Prong 1: Yes).
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 an equivalent of the words “apply it” and/or to instructions to implement an abstract idea on a computer (MPEP § 2106.05(f)). The instant claims recite the following additional elements:
Claim 8 recites “A system for virtual crossmatching using a physical-crossmatch-outcome-data-derived model, the system comprising: a computing platform including at least one processor; … implemented by the at least one processor for:”
Claims 9-14 recite “The system of claim 8/9/11/13 …”
Claim 13 recites “comprising an HLA data-preprocessor for: …”
Claim 14 recites “wherein the HLA data-preprocessor is configured for …”
Claim 15 recites “A non-transitory computer readable medium having stored thereon executable instructions that when executed by a processor of a computer control the computer to perform steps comprising: …”
Claims 16-21 recite “The non-transitory computer readable medium of claim 15/16/18/20 …”
It is noted that claims 1-7 do not recite any additional elements and are thus not being analyzed under Step 2A, Prong 2.
Regarding the above cited limitations in claims 8-21 of (i) a system comprising a computing platform with at least one processor, (ii) implemented by the at least one processor, (ii) an HLA data pre-processor, (iv) and a non-transitory computer readable medium having stored thereon executable instructions. These limitations are being interpreted as components of a generic computing system. This interpretation is reinforced by Figure 4. As such, these limitations equate to instructions to implement an abstract idea on a generic computer, which the courts have established does not render an abstract idea eligible in Alice Corp. 573 U.S. at 223, 110 USPQ2d at 1983. Furthermore, MPEP 2106.05(f)(2) recites that the use of a computer in its ordinary capacity to perform task such as receive, store, or transmit data does not integrate a judicial exception into a practical application.
As such, claims 1-21 are directed to an abstract idea and a natural phenomenon (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 instructions to apply the recited exception in a generic way and/or in a generic computing environment (MPEP § 2106.05(f)) and to well-understood, routine and conventional (WURC) limitations (MPEP § 2106.05(d)). The instant claims recite the following additional elements:
Claim 8 recites “A system for virtual crossmatching using a physical-crossmatch-outcome-data-derived model, the system comprising: a computing platform including at least one processor; … implemented by the at least one processor for:”
Claims 9-14 recite “The system of claim 8/9/11/13 …”
Claim 13 recites “comprising an HLA data-preprocessor for: …”
Claim 14 recites “wherein the HLA data-preprocessor is configured for …”
Claim 15 recites “A non-transitory computer readable medium having stored thereon executable instructions that when executed by a processor of a computer control the computer to perform steps comprising: …”
Claims 16-21 recite “The non-transitory computer readable medium of claim 15/16/18/20 …”
It is noted that claims 1-7 do not recite any additional elements and are thus not being analyzed under Step 2B.
Regarding the above cited limitations in claims 8-21 of (i) a system comprising a computing platform with at least one processor, (ii) implemented by the at least one processor, (ii) an HLA data pre-processor, (iv) and a non-transitory computer readable medium having stored thereon executable instructions. These limitations are being interpreted as components of a generic computing system. This interpretation is reinforced by Figure 4. As such, these limitations equate to instructions to implement an abstract idea on a generic computing environment, which the courts have established does not provide an inventive concept in Intellectual Ventures I LLC v. Capital One Bank (USA), 792 F.3d 1363, 1367, 115 USPQ2d 1636, 1639 (Fed. Cir. 2015).
Regarding the above cited limitation in claims 15-21 of a non-transitory computer readable medium that stores computer-executable instructions, these limitations equate to storing information in memory, which the courts have established as a WURC function of a generic computer in Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015).
When these additional elements are considered individually and in combination, they do not provide an inventive concept because they all equate to WURC functions/components of a generic computer and/or generic computing system. 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 1-21 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 1, 6-8, 13-15 and 20-21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Anunciação et al. (“Anunciação”; Transplant immunology 33, no. 3 (2015): 153-158).
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.
Claims 1, 8 and 15:
A method for virtual crossmatching using a physical-crossmatch- outcome-data-derived model, the method comprising:
A system for virtual crossmatching using a physical-crossmatch- outcome-data-derived model, the system comprising: a computing platform including at least one processor; a physical-crossmatch-outcome-data-derived model implemented by the at least one processor for:
A non-transitory computer readable medium having stored thereon executable instructions that when executed by a processor of a computer control the computer to perform steps comprising:
Anunciação discloses EpVix (physical-crossmatch-outcome-data-derived model), a cloud-based tool for epitope reactivity analysis and epitope virtual crossmatching to identify low immunogenic risk donors for sensitized recipients (title). EpVix aims to accurately predicting negative crossmatches (abstract). EpVix is a cloud-based software with algorithms such as the HLAMatchmaker algorithm (abstract). A cloud-based software inherently requires a computer with a processor and non-transitory computer readable media to store the software.
receiving as inputs, human leukocyte antigen (HLA) antibody mean fluorescence intensity (MFI) data of a prospective tissue recipient and HLA typing data of a tissue donor;
EpVix takes as input a recipient’s histocompatibility exam results such as HLA typing and LSA panels, wherein the LSA panel produce HLA MFI values (pg. 154, sec. 3.2.1, para. 1) (Figure 1) as well as a donor’s HLA typing data (pg. 154, sec. 3.2.2, para. 3).
generating, based on the inputs and a physical-crossmatch-outcome-data-derived model, a predicted virtual crossmatch outcome for the prospective tissue recipient; and
Anunciação teaches that the EpViX software performs a virtual crossmatch of the donor's HLA against each recipient's serum (pg. 154, sec. 3.2.2, para. 3). Figure 2 shows that a red epitope-based virtual crossmatch (EvXM) “indicates that the recipient's serum shows DSA with reactive epitopes and an MFI value above five thousand, thereby excluding the recipient” (pg. 154, sec. 3.2.2, para. 3).
using the predicted virtual crossmatch outcome to inform a transplant decision for the prospective tissue recipient.
Anunciação teaches that EpVix helps transplants teams make safer and smarter decision (pg. 165, col. 1, para. 1), particularly for organ donor allocation (pg. 157, col. 1, para. 3). A representative case is described in section 3.2.4, where a female patient was identified as a match based upon the EvXM.
Claims 6, 13 and 20:
Regarding claims 6, 13 and 20, Anunciação teaches using as input recipient HLA typing and LSA panels (recipient HLA MFI data and recipient HLA typing data) (pg. 154, sec. 3.2.1, para. 1) (Figure 1) and donor HLA typing data (donor HLA typing) (pg. 154, sec. 3.2.2, para. 3) (Figure 2). Figure 2 shows a list of eplets derived from the inputs (a list of recipient and donor eplet data). EpViX produces a list of non-self eplets of each allele tested in the LSAB (removing, from the list, eplets that are common to the recipient and donor eplet data) (pg. 154, sec. 3.2.1, para. 1) (Figure 1). Figure 2 shows the eplets that are not common between a donor and recipient, identified as DSA, are inputted into the EpViX algorithm (pg. 154, sec. 3.2.2, para. 3) (pg. 154, sec. 3.2.4, para. 1).
Claims 7, 14 and 21:
The broadest reasonable interpretation of claims 7, 14 and 21 includes removing eplets from the list that do not exceed an MFI threshold (i.e., unverified). Anunciação teaches that the list of eplets can be filtered based upon an MFI value not exceeding a threshold, which is indicated by a blue number in the MFI column (Figures 1 and 2). Figure 1 shows that eplets identified as blue have an MFI value lower than the cutoff. The unacceptable filter in Figure 1 filters out of the blue eplets (unverified) and keeps the red and black eplets that are reactive (pg. 154, sec. 3.2.1, para. 1).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 2-3, 9-10 and 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Anunciação et al. (“Anunciação”; Transplant immunology 33, no. 3 (2015): 153-158), as applied above to claims 1, 8 and 15 in section in Claim Rejections - 35 USC § 102, in view of Alzahrani et al. (“Alzahrani”; In Transplantation Proceedings, vol. 51, no. 2, pp. 488-491. Elsevier, 2019).
The limitations of claims 1, 8 and 15 have been taught in the rejection above in section Claim Rejections - 35 USC § 102 by Anunciação.
Claims 2, 8 and 16:
Regarding claims 2, 8 and 16, the following limitation is being interpreted as a product by process limitation: “a threshold determined empirically from physical crossmatch outcomes of a plurality of patients”. MPEP 2113.I recites “The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In the instant case, the product is the “threshold” and the process previously performed to derive the product is “determined empirically from physical crossmatch outcomes of a plurality of patient”. As such, a reference that teaches a threshold for summed HLA DSA MFI values will read on this product by process limitation.
Anunciação uses an LSAB panel that tested anti-HLA antibodies against different HLA molecules, which have associated sets of eplets (Figure 1) (pg. 154, sec. 3.2.1, para. 1). Figure 2 shows HLA DSA MIF values (HLA DSA MFI values of the prosecutive tissue recipient). Anunciação also teaches a threshold for MFI in Figure 1 (optimal threshold model).
However, Anunciação does not teach summing and comparing HLA DSA MFI values to a threshold.
Alzahrani evaluates concordance between actual flow crossmatches (aFXMs) and virtual flow crossmatches (vFXMs) (abstract). Alzahrani teaches “A sum of multiple weak antibodies (MFI < 2000) that yield MFI of > 3000 was used to predict positivity for patients with multiple antibodies” (pg. 489, col. 1, para. 3).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified Anunciação’s EpViX by summing multiple weak antibodies that together yield MFI > 3000 because Alzahrani states that this predicts positivity for patients with multiple antibodies (pg. 489, col. 1, para. 3). There would have been a reasonable expectation of success to modify the EpViX algorithm to sum and compare DSA MFI values to a threshold because Anunciação shows in Figure 2 DSAs with associated MFI values, which could then be summed and compared to a threshold as taught by Alzahrani.
Claims 3, 10 and 17:
The broadest reasonable interpretation of claim 3 includes it not being required because it is a contingent limitation that is not performed when the condition precedent of the sum of the HLA DSA MFI values is less than the threshold. See MPEP 2111.04(II) regarding the broadest reasonable interpretation of contingent limitations in a method claim. However, in the interest of compact prosecution, claim 3 is being interpreted as required by the claim.
Regarding claims 3, 10 and 17, Anunciação uses EpViX for organ allocation (pg. 154, sec. 3.2), and states that when a recipient’s serum shows DSA with reactive epitopes and an MFI > 5,000, then the patient is not a match (pg. 154, sec. 3.2.2, para. 3).
Alzahrani teaches summing DSA MFI values and determining that a patient will have a positive reaction to a donor when the sum exceeds an MFI > 3,000 (pg. 489, col. 1, para. 3).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have determined that a patient is not a match in Anunciação when a sum of weak DSA MFI values exceeds a threshold because the patient would have been identified as positive, as taught by Alzahrani. One of ordinary skill in the art would have had a reasonable expectation of success for deciding not to perform a transplant on a patient with a cumulative DSA MFI value that exceeds a threshold because exceeding the threshold indicates a potential transplant rejection.
Claims 4-5, 11, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Anunciação et al. (“Anunciação”; Transplant immunology 33, no. 3 (2015): 153-158), as applied above to claims 1, 8 and 15 in section in Claim Rejections - 35 USC § 102, in view of Weimer et al. (“Weimer”; Human Immunology 79 (2018): 17; published online 31 August 2018).
The limitations of claims 1, 8 and 15 have been taught in the rejection above in section Claim Rejections - 35 USC § 102 by Anunciação.
Claims 4, 11 and 18:
Regarding claims 4, 11 and 18, Anunciação shows in Figure 2 HLA DSA MFI values sorted by an MFI cutoff (pg. 154, sec. 3.2.2, para. 3).
However, Anunciação does not teach calculating a weighted sum of HLA DSA MFI values, wherein applied weights are chosen to minimize a function of predicted median channel shifts (MCS) determined for the HLA DSA MFI values and true physical crossmatch MCS determined from HLA DSA MFI values for a set of patients.
Weimer discloses a data-driven algorithm (DDA) that predicts flow cytometric (FXM) outcomes using HLA MFI values and donor HLA typing (Aim section). Two datasets were used that contained FXM with single antigen bead data for both HLA class I and HLA class II antibodies (Methods section). Weimer teaches “The second DDA applied a least-squares regression model to the HLA locus-specific data (second data set) to predict the actual T or B cell MCS” (minimize a function of predicted median channel shifts (MCS) determined for the HLA DSA MFI values and true physical crossmatch MCS determined from HLA DSA MFI values for a set of patients) (Methods section). Weimer further teaches “The least-squares model increased accuracy to 93.6% and 97.2% for T and B cell MCS, respectively. Class I DSA influenced T and B cell MCS more than class II. The relative importance of an individual HLA locus on T cell prediction was found to be HLA-B > -A > -C. In the least-squares fitting, B64 had a large positive effect while A34 had a large negative effect on T cell MCS” (where weights applied to the HLA DSA MFI values are derived by selecting values for the weights) (Results section).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified Anunciação’s EpVix algorithm by using a least-squares model to generate a weighted sum of HLA DSA MFI values that minimizes the distance between predicted and true MCS by applying a weight to each antibody against a particular HLA allele group because Weimer states that Class I DSA influenced T and B cell MCS more than class II and the relative importance of an individual HLA locus on T cell prediction was found to be HLA-B > -A > -C (Results section).
One of ordinary skill in the art would have had a reasonable expectation of success for using least-squares to calculate a weighted sum of HLA DSA MFI values that minimizes the distance between predicted and true MCS when generating a virtual crossmatch because Weimer states that the method achieved high accuracy for their virtual crossmatch (Results section).
Claim 5:
The broadest reasonable interpretation of claim 5 includes it not being required because it is a contingent limitation that is not performed when the condition precedent of the median channel shift calculated for a patient does not exceed a median channel shift cutoff. See MPEP 2111.04(II) regarding the broadest reasonable interpretation of contingent limitations in a method claim. As such, claim 5 is rejected because it is not required and because claim 4, to which it depends, is rejected above.
Claims 12 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Anunciação et al. (“Anunciação”; Transplant immunology 33, no. 3 (2015): 153-158) in view of Weimer et al. (“Weimer”; Human Immunology 79 (2018): 17; published online 31 August 2018), as applied above to claims 8, 11, 15 and 18, and in further view of Schinstock et al. (“Schinstock”; Transplantation 101, no. 10 (2017): 2429-2439).
The limitations of claims 8 and 15 have been taught in the rejection above in section Claim Rejections - 35 USC § 102 by Anunciação.
The limitations of claims 11 and 18 have been taught in the rejection above by Anunciação and Weimer.
Regarding claims 12 and 19, Anunciação uses EpViX for organ allocation (pg. 154, sec. 3.2), and states that when a recipient’s serum shows DSA with reactive epitopes and an MFI > 5,000, then the patient is not a match (pg. 154, sec. 3.2.2, para. 3).
Weimer teaches applying a least-squares regression model to HLA locus-specific data to predict the actual T or B cell MCS (Methods).
However, neither Anunciação nor Weimer teach deciding to not perform a transplant if a MCS calculated for a patient exceeds a MCS cutoff.
Schinstock compares the outcomes of 954 patients transplanted with varied levels
of baseline DSA detected by single antigen beads and B flow cytometric crossmatch (abstract). Schinstock states “A mean channel fluorescence shift greater than 106 for was considered positive for B cells” (pg. 2430, col. 1, last para.)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have determined that a recipient is not a transplant match using predicted and true MCS, as taught by Anunciação and Weimer, when the recipient’s predicted MCS exceeds a MCS greater than 106 because Schinstock states that this indicates a recipient is positive for B cells (pg. 2430, col. 1, last para.). One of ordinary skill in the art would have had a reasonable expectation of success for deciding not to perform a transplant on a recipient with a predicted MCS that exceeds a 106 cutoff because exceeding the threshold indicates a potential transplant rejection.
Conclusion
No claims are allowed.
Notable, but not relied upon, prior art includes the following:
Sullivan et al (Human Immunology 79, no. 10 (2018): 711-715) who discloses “FlowPRA screening results (Class I and II), the presence or absence of DSA(s), and corresponding MFI values were also evaluated in the comparison of FCXM with the vXM” (abstract).
Tambur et al. (American Journal of Transplantation 9, no. 8 (2009): 1886-1893) who discloses “The goal of this work was to evaluate concordance between (a) actual flow cytometric crossmatch (FCXM) that is performed by the OPO laboratory servicing our transplant center and (b) virtual XM (vXM) prediction based on antibody identification by solid-phase methods performed in our laboratory” (abstract).
Roux et al. (Frontiers in medicine 4 (2017): 155) who discloses “Comparison of DSA MFI from SAB tests and from a complement binding test suggested that the MFI of immunodominant DSA or the sum MFI of all DSA may be as efficient as the complement binding test for AMR prediction and graft failure” (pg. 2, col. 1, para. 2).
Webber et el. (American Journal of Transplantation 18, no. 9 (2018): 2148-2162) who discloses “We chose to assess DSA strength using MFI cutoffs of 1000, 4000, and 8000. These values were determined a priori and were based on the observed distribution of MFI values as well as our prior experience with prediction of flow and CDC-crossmatch results based on strength of DSA” (pg. 2161, col. 1, para. 2).
Peng et al. (NPL ref. 4 on IDS filed 05/10/2022; Medical Science Monitor: International Medical Journal of Experimental and Clinical Research 25 (2019): 952) who discloses “Physical crossmatch (PXM) and virtual crossmatch (VXM) are applied to identify preexisting donor-specific human leukocyte antigen (HLA) antibodies in patients awaiting kidney transplantation” (abstract).
Althaf et al. (World Journal of Transplantation 7, no. 6 (2017): 339) who discloses a review on HLA typing and crossmatches and teaches “Mismatch for different HLA antigens does not have equal weight. We know from the initial Collaborative Transplant Study (CTS) analysis that HLA-DR and HLA-B antigens offer the most alloimmune burden with less so from HLA-A” (pg. 341, col. 2, para. 1).
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/N.A.A./Examiner, Art Unit 1687
/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685
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