DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Claims 1-56 are cancelled.
Claims 57-92 are pending.
Claims 57-92 are rejected.
Claims 57-61, 63, and 72 are objected to.
Priority
Applicant’s claim for the benefit of a prior-filed application, PCT/IB2020/060191 filed 30 Oct. 2020, under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Acknowledgment is made of applicant’s claim for foreign priority to AU2019904119 filed 31 Oct. 2019 under 35 U.S.C. 119 (a)-(d). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Accordingly, the effective filing date of the claimed invention is 31 Oct. 2019.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 28 April 2022 and 29 March 2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the list of cited references was considered in full by the examiner.
Drawings
The replacement drawing sheets filed 21 Dec. 2022 have been entered.
The drawings filed 21 Dec. 2022 are objected to because:
Figures 1-12 fail to comply with 37 CFR. 1.84(u)(1), which states view numbers must be preceded by the abbreviation “FIG.”. The figures should be relabeled “FIG. 1”, “FIG. 2”, etc.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code at pg. 55, lines 8-10 and 28 and pg. 56, lines 1, 4, and 7.. 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.
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.
The abstract of the disclosure is objected to because:
The abstract includes language which can be implied, including “The present disclosure relates to…” in line 1.
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).
Claim Objections
Claims 57-61, 63, and 72 are objected to because of the following informalities:
Claim 57 recites “c) determining…as a transplant match for a recipient in need…”. To increase clarity and use consistent language, the claim should be amended to recite “match for the recipient in need…”.
Claims 58-61 recite “c) determining gene dosage for each…”, which is a grammatical error and should recite “c) determining a gene dosage for each…”.
Claims 58-61 recite “d)…the gene dosage for each of the locus of the gene complex”, which is grammatically incorrect and should recite “for each locus of the gene complex” or “for each of the loci of the gene complex”.
Claim 61 recites “ e)…, using a computer; wherein…, and selecting…”. To fix a grammatical error and use consistent language, claim 61 should be amended to recite e), using a computer[[;]], wherein….[[,]]; (f) selecting….”.
Claim 63 recites “wherein the gene dosage for each locus is copy number..”, which is a grammatical error and should recite “is a copy number”.
Claim 72 recites “…wherein the step of a) generating…from a nucleic acid sample obtained from the one or more potential transplant donors…comprises: a) contacting a nucleic acid sample from the one or more transplant donors…”, which should be amended to recite “…comprises: a) contacting [[a]] the nucleic acid sample from…” to increase clarity and use consistent language.
Claim 72 recites “…togene target sequences” in line 5, which should recite “to gene target sequences’.
Appropriate correction is required.
Claim Objection Warning:
Applicant is advised that should claim 58 be found allowable, claims 59-60 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
In the instant case, the only difference in wording between claims 58 and 60 is an intended use of the claimed invention within the preambles of the claim. Similarly, the only difference in wording between claims 58 and 59 are the final wherein clauses in the claim. However, the wherein clause of claim 58 states the gene dosage maps of the donor and recipient being correlated identifies a transplant match, which would inherently represent a reduced risk of graft versus host disease as in claim 59. Therefore, the claims are considered substantial duplicates.
Claim Interpretation
Applicant’s specification at pg. 21, lines 8-13 defines “gene dosage” to refer to the number of copies of a particular gene present in a genome.
Applicant’s specification at pg. 21, lines 14-17 defines “gene dosage map” to refer to a pictorial showing the relative amounts of each and every loci of a gene complex relative to each other.
Claims 57-61 recite the term “gene complex”. In light of Applicant’s specification at pg. 23, lines 12-14, the term is interpreted to refer to a group of related genes that act as a functional unit, such as the HLA gene complex or MHC gene complex.
Claims 58 and 60 recite “wherein the one or more potential transplant donors is identified as a transplant match and/or best transplant match for a recipient in need of a transplant if the gene dosage map of the one or more transplant donors correlates with the gene dosage map of the recipient”. The above wherein clause is interpreted to recite an intended result of the process step of “e) comparing the generated dosage map…”, but the claims do not require a step of identifying a transplant match and/or best transplant match. See MPEP 2111.04 I.
Claims 66 and 73 recite “a highly polymorphic gene complex”, which is defined in Applicant’s specification at pg. 43, lines 22-24 to refer to genes that have greater levels of polymorphism in the coding region of the gene compared to the non-coding regions.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 58-62, 69-85, and 89-92 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed, had possession of the claimed invention.
Claims 58-61, and claims dependent therefrom, recite “a) generating sequences of a gene complex, using a computer, from a nucleic acid sample…”, which encompasses using a generic computer to sequence a nucleic acid sample.
A claim term is functional when it recites a feature "by what it does rather than by what it is" (e.g., as evidenced by its specific structure or specific ingredients). In re Swinehart, 439 F.2d 210, 212, 169 USPQ 226, 229 (CCPA 1971). Computer-implemented functional claim limitations may also be broad because the term "computer" is commonly understood by one of ordinary skill in the art to describe a variety of devices with varying degrees of complexity and capabilities. However, unlimited functional claim limitations that extend to all means or methods of resolving a problem may not be adequately supported by the written description. See MPEP 2173.05(g) and 2114 IV.
In the instant case, Applicant’s specification at pg. 28, lines 10-11 and 25-26, pg. 29, lines 13-14, pg. 30, lines 21-22, and pg. 39, lines 1-5 discloses sequences can be generated from a nucleic acid sample, including using hybridization-based enrichment sequencing and next generation sequencing. Applicant’s specification at pg. 41 line 28 to pg. 42, line 2 and pg. 43, lines 5-9, provide support for a “sequencing platform” that performs sequencing, including various Illumina platforms, of MiSeq, iSeq, or MiniSeq systems. However, the specification does not provide support for all computers that may generate a sequence from a nucleic acid sample.
For the reasons discussed above, the specification does not provide a sufficient disclosure of the limitation of claims 58-61, and claims dependent therefrom, above to demonstrate to one of ordinary skill in the art that the inventor possessed the invention at the time the application was filed. For more information regarding the written description requirement, see MPEP §2161.01- §2163.07(b).
To overcome the rejection, the claims may be amended to recite that the sequences are generated “using a sequencing platform”.
Claim Rejections - 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.
Claims 57-92 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention.
Claim 57, and claims dependent therefrom, are indefinite for recitation of “b)…the gene dosage maps of the one or more potential donors and the recipient…;c) determining….the gene dosage map of the one or more transplant donors…with the gene dosage map of the recipient, wherein… the closer the correlation between the gene dosage maps of the one or more donors compared to the recipient”. Claim 57 previously recites “generating a gene dosage map…for each gene locus of a gene complex for the one or more potential donors and the recipient”, but does not recite generating a gene dosage map for each of the one or more donors and the recipient. It is unclear if claim 57 intends to (1) determine a single gene dosage map for the one or more transplant donors and a single gene dosage map for the recipient, suggested in steps d) or if claim 57 intends or (2) determine a gene dosage map for each locus of a gene complex for the one or more donors and the recipient. If Applicant intends (2), then it is not clear what gene dosage maps are being referred to in step c) (e.g. which locus or loci). Clarification is requested. For purpose of examination, the claim is interpreted to determine a gene dosage map for each of the one or more potential donors and the recipient, using each locus of a gene complex.
Claims 57-61 are indefinite for recitation of “each locus of the gene complex”. It is unclear which set of loci, “each locus” is referring to because the claims do not previously recite any loci of the gene complex. Furthermore, it is not clear the claims intend to sequence or analyze the entire gene complex, given dependent claims further limit sequencing of the gene complex to involve sequencing “an HLA gene exon” or sequencing “an entire HLA gene complex” (see dependent claims 78-79). As a result, it is not clear that “each locus” is intended to refer to all loci of the gene complex rather than some subset of loci (e.g. loci of exons). It is noted that if Applicant does intend for “each locus of the gene complex” to refer to all positions of the gene complex, then at least claim 77 would fail to further limit claim 72, since claim 58 would already require the entire gene complex, including all exons, were sequenced (and the gene complex already pertains to transplantation as described in the final wherein clause of claim 58). Claim 78 would also fail to further limit claim 72 for similar reasons. For purpose of examination, the claims are interpreted to mean “each locus of a plurality of loci of the gene complex”.
Claims 58-61 is indefinite for recitation of “b) assigning a plurality of the sequences generated in step (a) corresponding to each locus…. The metes and bounds of the claims are unclear because step b) does not clearly specify what the plurality of sequences are being assigned to. As written, it is not clear if Applicant intends to assign the sequences of (a) to each locus of the gene complex, or if Applicant intends to assign sequences corresponding to each locus to some other entity. Clarification is requested via claim amendment. In light of Applicant’s specification, sequences are interpreted to be assigned to each locus.
Claims 58-61 are indefinite for recitation of “e)…the generated gene dosage map of the one or more transplant donors with the generated gene dosage map of the recipient”. There is insufficient antecedent basis for two separate gene dosage maps, because claims 58-61 previously recite “d) generating a gene dosage map of the gene complex for the one or more transplant donors and the recipient”, such that only a single gene dosage map may be determined for the one or more transplant donors and the recipient. If Applicant intends for a gene dosage map to be determined for each of (1) the one or more transplant donors and (2) the recipient, then it is further unclear in what way two separate dosage maps are obtained using “the gene dosage for each…locus of the gene complex” (i.e. using only a single gene dosage for each locus). Clarification is requested via claim amendment. If Applicant intends to determine a gene dosage map for each of the one or more transplant donors and the recipient, Applicant may amend step c) to clarify that a gene dosage for each of (1) the one or more transplant donors and (2) the recipient is determined for each locus of the gene complex, and similarly in step d), that a gene dosage map of the gene complex is generated for each of (1) the one or more potential transplant donors and (2) the recipient from the respective gene dosage for each locus.
Claim 59 is indefinite for recitation of “a)…the one or more potential transplant donors …”. There is insufficient antecedent basis for this limitation in the claim because claim 59 does not previously recite any potential transplant donors.
Claim 62 is indefinite for recitation of “…wherein generating the gene dosage map for each locus…for the one or more potential donors and the recipient…”. Claim 58, from which claim 62 depends, recites “d) generating a gene dosage map of the gene complex for the one or more potential transplant donors and the recipient from the gene dosage for each of the locus…”, but does not generate a gene dosage map for each locus. Therefore, it is not clear if claim 62 intends to further limit the gene dosage map of the one or more transplant donors and the gene dosage map of the recipient, or if claim 62 intends to require generating a gene dosage map for each locus in addition to the donor(s) and recipient. For purpose of examination, claim 62 will be interpreted to further limit the gene dosage map of the one or more transplant donors and the gene dosage map of the recipient to be determined as claimed.
Claim 63 is indefinite for recitation of “wherein the gene dosage for each locus is copy number for…all loci..”. It is unclear in what way a gene dosage for a given locus is intended to be a copy number for all loci. As a result, it is also unclear if the gene dosage is intended to be for each locus, or if there is a single gene dosage for all loci. Clarification is requested.
Claim 63 is indefinite for recitation “wherein the gene dosage for each locus…”. There is insufficient antecedent basis for this limitation in the claim because claim 57, from which claim 63 depends, does not recite a gene dosage for each locus, and instead only recites “a gene dosage map…for each locus”. Therefore, it is not clear if claim 63 is intending to refer to the “gene dosage map” of each locus, or a specific gene dosage for a locus. As already discussed above for claim 57, it is not clear that Applicant intends to actually determine a gene dosage map for each locus, and therefore, claim 63 is interpreted to mean the gene dosage map for the one or more potential donors and the recipient comprises a gene dosage for each locus, wherein the gene dosage of each locus is a copy number for the respective locus, or all loci, of the gene complex.
Claim 72, and claims dependent therefrom, are indefinite for recitation of “b) enriching a nucleic acid by hybridizing the nucleic acid to one or more oligonucleotide probes; c) separating nucleic acid hybridized to the one or more oligonucleotide probes from nucleic acid not hybridized to the one or more oligonucleotide probes…”. Claim 72 previously recites “a) contacting a nucleic acid sample…with oligonucleotide probes, wherein the oligonucleotide probes hybridize to gene target sequences…”. Therefore, both steps a) and b) involve hybridizing oligonucleotide probes to nucleic acid. As a result, it is not clear if “the one or more oligonucleotide probes” recited in steps c)-d) are referring to oligonucleotide probes in step a) or step b), and furthermore, if there are required to be multiple probes (as in step a)) or if that may be a single probe (as in step b)). Last, it is unclear if Applicant intends to have two separate steps of contacting nucleic acid to oligonucleotide probes (in steps a) and b), or if the “nucleic acid” and probes of step b) are intended to be the same nucleic acid and probes as in step a). Clarification is requested via claim amendment. Claims 76 and 79 also recite “the one or more oligonucleotide probes” and thus is indefinite for the same reasons discussed above for claim 72.
Claim 83 is indefinite for recitation of “..wherein the nucleic acid sample from the one or more transplant donors and the recipient in need of a transplant that is contacted with the one or more oligonucleotide probes…”. There is insufficient antecedent basis for the nucleic acid sample from the one or more transplant donors and the recipient in need of a transplant that is contacted with the one or more oligonucleotide probes because claim 72 recites “a) contacting a nucleic acid sample from the one or more transplant donors and the recipient with oligonucleotide probes, wherein the oligonucleotide probes hybridize to gene target sequences…”, and then a separate step “b) enriching a nucleic acid by hybridizing the nucleic acid to one or more oligonucleotide probes” (a different set of probes). However, claim 72 does not recite contacting the one or more oligonucleotide probes (of step b of claim 72) to the nucleic acid sample from the transplant donor(s) and recipient.
Claim 84 is indefinite for recitation of “the nucleic acid sample is fragmented before or after being contacted with the one or more oligonucleotide probes” for the same reasons discussed above for claim 83. The claim is interpreted to mean “contacted with the oligonucleotide probes”.
Claim 86, and claims dependent therefrom, are indefinite for recitation of “the nucleic acid sample from the one or more transplant donors and the recipient…”. There is insufficient antecedent basis for this limitation in the claim because claim 57, from which claim 86 depends, does not recite a nucleic acid sample from the one or more transplant donors and the recipient. For purpose of examination, the limitation is interpreted to define the process in which the “loci-assigned sequences” were previously generated, given claim 57 does not recite any step of generating sequences from the nucleic acid sample.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 64-65, 67, and 74 are rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 64 recites “…wherein the copy number for each locus and all loci of the gene complex allows determination of zygosity for each locus and all loci of the gene complex”.
Claim 65 recites “wherein the copy number of each locus and all loci of the gene complex allows determination of whether two alleles have an identical sequence. MPEP 2111.04 I. states the court noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’. In the instant case, the wherein clause of claims 64-65 merely express the intended result or use of the copy numbers recited in claim 63, which does not have patentable weight. Therefore, claims 64-65 fail to further limit the subject matter of claim 63, from which it depends.
Claims 67 and 74 recites “wherein the gene complex is a gene complex pertaining to transplantation”. Claim 57, from which claim 67 depends, recites “generating a gene dosage map…for each locus of a gene complex” and “…the closer the correlation between the gene dosage maps of the one or more donors compared to the recipient, the higher the probability of the one or more donors being a transplant match….”. Claim 58, from which claim 74 ultimately depends similarly recites a transplant match is identified if the gene dosage map of the gene complex of the one or more donors correlates with the gene dosage map of the gene complex of the recipient. Therefore, claims 57-58 already requires the gene complex pertains to transplantation, given a gene dosage map of the gene complex is correlated with a probability of a transplant match or is associated with a best match. As a result, claims 67 and 74 fail to further limit the subject matter of claims 57 and 58, from which they respectively depend.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 57-92 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions without significantly more.
The Supreme Court has established a two-step framework for this analysis, wherein a claim does not satisfy § 101 if (1) it is “directed to” a patent-ineligible concept, i.e., a law of nature, natural phenomenon, or abstract idea, and (2), if so, the particular elements of the claim, considered “both individually and as an ordered combination,” do not add enough to “transform the nature of the claim into a patent-eligible application.” Elec. Power Grp., LLC v. Alstom S.A., 830 F.3d 1350, 1353 (Fed. Cir. 2016) (quoting Alice, 134 S. Ct. at 2355). Applicant is also directed to MPEP 2106.
Step 1: The instantly claimed invention (claims 57-61 being representative) is directed to a method of identifying a transplant donor and preventing graft versus host disease (GVHD). Therefore, the instantly claimed invention falls into one of the four statutory categories. [Step 1: YES]
Step 2A: First it is determined in Prong One whether a claim recites a judicial exception, and if so, then it is determined in in Prong Two if the recited judicial exception is integrated into a practical application of that exception.
Step 2A, Prong 1: Under the MPEP § 2106.04, the Step 2A (Prong 1) analysis requires determining whether a claim recites an abstract idea, law of nature, or natural phenomenon.
Claim 57 recites the following steps which fall under the mathematical concepts and/or mental processes groupings of abstract ideas:
a) generating a gene dosage map… for each locus of a gene complex for the one or more potential donors and the recipient based on loci-assigned sequences (mental process and mathematical concept);
b) comparing the gene dosage maps of the one or more potential donors and the recipient…. (mental process); and
c) determining one or more transplant donors as a transplant match for a recipient in need of a transplant if the gene dosage map of the one or more transplant donors correlates with the gene dosage map of the recipient in need of a transplant…wherein the closer the correlation between the gene dosage maps of the one or more donors compared to the recipient, the higher the probability of the one or more donors being a transplant match and/or best transplant match for the recipient (mental process and mathematical concept).
Claims 58-61 recite the following steps which fall under the mathematical concepts, mental processes, and/or certain methods of organizing human activity groupings of abstract ideas:
b) assigning a plurality of the sequences generated in step (a) corresponding to each locus of the gene complex…(mental process);
c) determining gene dosage for each locus of the gene complex from the plurality of sequences assigned in step (b)… (mental process and mathematical concept);
d) generating a gene dosage map of the gene complex for the one or more potential transplant donors and the recipient from the gene dosage for each of the locus of the gene complex determined in step (c)…. (mental process and mathematical concept); and
e) comparing the generated gene dosage map of the one or more potential transplant donors with the generated gene dosage map of the recipient…(mental process).
wherein the one or more potential transplant donors is identified as a transplant match and/or best transplant match for a recipient in need of a transplant if the gene dosage map of the one or more transplant donors correlates with the gene dosage map of the recipient (claims 58 and 60);
wherein the gene dosage map of the one or more potential transplant donors correlating with the gene dosage map of the recipient in need of a transplant is indicative of reduced likelihood of the transplant recipient developing graft versus host disease following transplantation of a graft from the one or more transplant donors (claims 59 and 61); and
f) selecting graft and/or tissue and/or organ from a transplant donor having a gene dosage map that correlates with the gene dosage map of the recipient for transplant to the recipient (claim 61 only) (mental process).
The identified claim limitations falls into the group of mental processes for the following reasons. In this case, assigning sequences to each locus of the gene complex encompasses analyzing aligned locations of each sequence to determine sequences that are within a given locus, which can be practically performed in the mind. Determining a gene dosage for each locus of the gene complex and then generating a gene dosage map from the gene dosage encompasses counting a total number of reads assigned to each locus and dividing the total number by an average read depth of a reference region or genome to obtain a gene dosage, and then organizing the information into an graph depicting the relative counts, which can be practically performed in the mind aided with pen and paper. Comparing the generated dosage map of the one or more potential transplant donors with the generated dosage map of the recipient is simply a mental step of comparing information. Last, determining one or more transplant donors as a transplant match if the gene dosage map of a donor correlates with the gene dosage map of a recipient can be practically performed in the mind by comparing the gene dosage of each locus in the dosage map between the donor and recipient to determine if they are correlated. That is, other than reciting the steps are carried out by a computer, nothing in the claims precludes the steps from being practically performed in the mind.
The identified claim limitations falls into the group of mathematical concepts for the following reasons. The step of determining a gene dosage for each locus and gene dosage map requires performing mathematical calculations as defined in Applicant’s specification at pg. 21, lines 8-17, which states the gene dosage map shows the relative amounts of each and every loci of a gene complex relative to each other and that the gene dosages are relative amounts (e.g. division). Similarly, the step of determining a transplant donor as a match if the dosage map of a donor correlates with the dosage map of the recipient encompass calculating a similarity between the dosage maps, as defined in Applicant’s specification at pg. 25, lines 10-14. Therefore, these limitations recite a mathematical concept.
Dependent claims 62-69, 71, 73-75, and 86-88 further recite an abstract idea and/or are part of the abstract idea set forth above. Dependent claim 62 further limits the abstract idea of generating the gene dosage map to comprise dividing sequences. Dependent claims 63 further limits the abstract idea of generating the gene dosage maps to comprise a copy number gene dosage for each locus. Dependent claims 64-65, fail to further limit the subject matter of claim 63 from which they depend, and thus are part of the abstract idea of generating the gene dosage maps. Dependent claims 66, 68, 73, and 75 further limit the gene complex being analyzed in the independent claims, and thus are part of the abstract idea. Dependent claims 67 and 74 fail to further limit the gene complex of claim 57 and thus are part of the abstract idea of claims 57 and 58. Dependent claim 69 further limits the mental process of assigning to be based on or more regions of each locus. Dependent claim 71 further recites the mental process of sequencing editing and alignment (i.e. data comparisons). Dependent claims 86-88 further limit the process in which the loci-assigned sequences were previously generated (see 112(b) interpretation above), and thus are part of the abstract idea of generating the gene dosage maps of claim 57.
Last, the claims further recite the law of nature of a natural correlation between copy numbers (i.e. gene dosages) of a gene complex, including HLA, and transplant donor compatibility or graph versus host disease (GVHD), analogous to 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). See MPEP 2106.04(b).
Therefore, claims 57-92 recite an abstract idea and law of nature. [Step 2A, Prong 1: YES]
Step 2A: Prong 2: Under the MPEP § 2106.04, the Step 2A, Prong 2 analysis requires identifying whether there are any additional elements recited in the claim beyond the judicial exception(s), and evaluating those additional elements to determine whether they integrate the exception into a practical application of the exception. This judicial exception is not integrated into a practical application for the following reasons.
The additional elements of claims 57-61 include:
a computer; and
a) generating sequences of a gene complex, using a computer (sequencer), from a nucleic acid sample obtained from the one or more potential transplant donors and the recipient.
The additional elements of claims 70-71 and 91-92;
a computer program (claims 70-71);
sequences are generated in computer readable form of a FASTQ (claims 91-92);
The additional elements of claim 72 include:
a) contacting a nucleic acid sample from the one or more transplant donors and the recipient with oligonucleotide probes, wherein the oligonucleotide probes hybridize to gene target sequences in the nucleic acid sample;
b) enriching a nucleic acid by hybridizing the nucleic acid to one or more oligonucleotide probes;
c) separating nucleic acid hybridized to the one or more oligonucleotide probes from nucleic acid not hybridized to the one or more oligonucleotide probes; and
d) sequencing the enriched nucleic acid to identify one or more gene alleles; wherein the gene target sequences are in a non-coding region of the gene.
The additional elements of claims 76-85 and 89-90 include:
amplifying the nucleic acid bound to the one or more oligonucleotide probes (claim 76);
sequencing an HLA gene exon, or a gene exon pertaining to transplantation (claim 77);
sequencing an entire HLA gene complex, or any entire gene complex pertaining to transplantation (claim 78);
wherein the one or more oligonucleotide probes comprises a capture tag (claim 79);
wherein the capture tag is biotin or streptavidin (claim 80);
contacting the capture tag with a binding agent (claim 81);
wherein the binding agent is biotin or streptavidin (claim 82);
wherein the nucleic acid sample from the one or more transplant donors and the recipient in need of a transplant that is contacted with the one or more oligonucleotide probes comprises single stranded nucleic acid (claim 83);
wherein the nucleic acid sample is fragmented before or after being contacted with the one or more oligonucleotide probes (claim 84);
wherein the fragments of the nucleic acid sample have an average length greater than about 100 bp (claim 85);
wherein sequencing is performed using high-throughput sequencing (claim 89); and
wherein the high-throughput sequencing is hybrid-capture next generation sequencing (claim 90);
Regarding the additional elements of claims 57-61, 70-71, and 91-92 of a computer used to carry out the abstract idea, computer programs, and computer-readable form, the courts have found the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not integrate a judicial exception into a practical application. See MPEP 2106.05(f).
The additional elements of claims 58-61, 72, 76-85, and 89-90, of fragmenting the nucleic acid sample to an average length of greater than 100 bp before contacting, contacting single-stranded nucleic acids of the one or more transplant donors and the recipient to one or more oligonucleotide probes comprising a biotin or streptavidin capture tag, contacting the capture tag with a biotin or streptavidin binding agent, enriching for nucleic acid bound to the probes, amplifying the nucleic acid bound to the probes, and then performing hybrid-capture next generation sequencing on the captured nucleic acid is not sufficient to integrate the recited judicial exception into a practical application for the following reason. The limitations only serve to collect data for use by the abstract idea, which amounts to insignificant extra-solution activity that is not sufficient to integrate the recited judicial exception into a practical application. See MPEP 2106.05(g).
Last, the additional element of claim 92 of the generated sequences being stored in a FASTQ file only serves to generally link the abstract idea of analyzing sequences to a computer technological environment, which is not sufficient to integrate the judicial exception into a practical application. See MPEP 2106.05(h).
Therefore, the additionally recited elements merely invoke computers as tool to carry out the abstract idea, amount to insignificant extra-solution activity, and/or generally link the abstract idea to a technological environment, and as such, the claims as a whole do no integrate the abstract idea into practical application. Thus, claims 57-92 are directed to an abstract idea and law of nature. [Step 2A, Prong 2: NO]
Step 2B: In the second step it is determined whether the claimed subject matter includes additional elements that amount to significantly more than the judicial exception. See MPEP § 2106.05.
The additional elements are outline in the Step 2A, Prong 2 section above.
The claims do not include any additional steps appended to the judicial exception that are sufficient to amount to significantly more than the judicial exception for the following reasons.
Regarding the additional elements of a computer used to carry out the abstract idea, computer programs, and computer-readable form, the courts have found the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not provide significantly more. See Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone); TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit).
Furthermore, regarding the computer-readable FASTQ file of claims 91-92, Applicant’s specification at pg. 56, lines 5-10 discloses commercially available software that processes raw sequencing data in FASTQ file format, demonstrating the conventionality of the file format. Furthermore, Applicant’s specification also provides no detail as the actual format of FASTQ files, demonstrating that the element is so well-known that it need not be described in detail in the patent specification. SEE MPEP 2106.05(d) I.
The additional elements of claims 58-61, 72, 76-85, and 89-90, of fragmenting the nucleic acid sample to an average length of greater than 100 bp before contacting, contacting single-stranded nucleic acids of the one or more transplant donors and the recipient to one or more oligonucleotide probes comprising a biotin or streptavidin capture tag, contacting the capture tag with a biotin or streptavidin binding agent, enriching for nucleic acid bound to the probes, and then performing hybrid-capture next generation sequencing on the captured nucleic acid describes a well-understood, routine, and conventional hybrid-capture sequencing process. This position is supported by Applicant’s own specification, Nagymihaly et al. (Next-generation Sequencing and its new possibilities in medicine, 2015, Acta Biologica Szegediensis, pg. 323-339), Koboldt et al. (The Next-Generation Sequencing Revolution and Its Impact on Genomics, 2013, Cell, 155, pg. 27-38), and Yang et al. (Transplant genetics and genomics, 2017, Nature Reviews Genetics, 18, pg. 309-326).
First, Applicant’s specification at pg. 37, lines 8-19 discloses the nucleic acid may be fragmented by physical shearing, sonication, restriction digestion, or other suitable technique known int eh art, and at pg. 37 line 30 to pg. 38 line 3 that nucleic acid can be made single stranded using techniques known in the art. Applicant’s specification at pg. 39, lines 5-22 also describes hybridization conditions that are well-known in the art, demonstrating the conventionality of hybridization techniques.
Furthermore, Nagymihaly reviews next-generating sequencing techniques, and discloses high-throughput DNA sequencing is routinely used on a wide range of important fields in biology (Abstract). Nagymihaly discloses targeted enrichment sequencing techniques are based on either PCR or hybridization, and to capture a target sequence in hybridization, genomic DNA is sheared and processed into a sequencing library, library fragments are subject to hybridization to biotin-labelled oligonucleotide probes specific for target regions, and the biotin-labeled probes bind to streptavidin-coated magnetic beads (pg. 331, col. 2, para. 2). Nagymihaly discloses that, at the end, library fragments are removed from their binding and are sequenced (pg. 331, col. 2, para. 2). Nagymihaly further discloses that DNA samples must be fragmented into small pieces from 100-800 base pairs before sequencing (pg. 324, col 1.para. 2 and col. 2, para. 3).
Kobolt similarly reviews next-generation sequencing and its impact on genomics (Abstract), and discloses genomic technologies including hybrid capture, which involves capturing DNA fragments using probes linked to biotin molecules and mixing the probe:library complexes with streptavidin-coated magnetic beads to selectively capture targeted regions of the genome (pg. 27, col. 2, para. 1). Kobolt similarly discloses subsequent denaturation releases the captured library fragments, so they’re ready for postcapture amplification and sequencing (pg. 27, col. 2, para. 1), demonstrating the conventionality of amplifying the enriched nucleic acids before sequencing. Therefore, the additional elements above pertaining to sample preparation and high throughput hybrid-capture sequencing of nucleic acid are well-understood, routine, and conventional.
Last, Yang reviews genetic analysis in transplantation (Abstract), and discloses the HLA complex in humans is the most immunologically and clinically relevant regions in the context of transplantation (pg. 309, col. 2, para. 3 to pg. 310, col. 1, para. 1). Yang discloses variations in HMC genes, including HLA-A, HLA-B, and HLA-DR have the greatest importance for successful HLA matching, and when HLA is matched, graft survival decreases in a manner that is dependent on the number of mismatches (i.e. HLA genes are analyzed in the donor and recipient) (pg. 311, col. 2, para. 2 to pg. 312, col. 1, para. 1). Yang further discloses that numerous methodologies have been developed for high-throughput typing of HLA genes, including using next-generation sequencing methods, and sequencing panels targeted at HLA loci have become routinely available in the clinic. (pg. 312, col. 1, para. 2). Therefore, even considering the additional elements in combination, performing targeted sequencing, such as hybrid-capture, on HLA loci in transplant donors and recipients is well-understood, routine, and conventional.
Taken alone, the additional elements do not amount to significantly more than the above-identified judicial exception(s). Even when viewed as a combination, the additional elements fail to transform the exception into a patent-eligible application of that exception. Thus, the claims as a whole do not amount to significantly more than the exception itself. [Step 2B: NO]
Therefore, the instantly rejected claims are not drawn to eligible subject matter as they are directed to an abstract idea and natural correlation without significantly more. For additional guidance, applicant is directed generally to applicant is directed generally to the MPEP § 2106.
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.
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 57-70, 86-88, and 91 are rejected under 35 U.S.C. 103 as being unpatentable over McCaroll (2017) in view of Jan (2019), as evidenced by McGranahan (2017).
Cited references:
McCarroll et al., US 2007/0172853 A1;
Jan et al., Recurrent genetic HLA loss in AML relapsed after matched unrelated allogeneic hematopoietic cell transplantation, 2019 July, Blood Advances, 3(14), pg. 2199-2204; and
McGranahan et al., Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution, 2017, Cell, 171, pg. 1259-1271.
Regarding claim 57, McCarroll discloses a method for predicting the immuno-compatibility between a first subject that is a transplant recipient and a second subject that is a donor (Abstract; [0003]-[0004]; claim 19), wherein the method comprises the following steps:
McCarroll discloses a) determining a deletion variant pattern for the first and second subjects (i.e. the donor and recipient) ([0019]), wherein a deletion variant pattern is a compilation of the determination of the presence or absence of deletion variants in the genes of a respective biological sample and includes relative copy numbers ([0037]; [0170] and Figure 4, e.g. determined deletion genotypes include 0 or 1 copy of the gene). McCaroll discloses the deletion variant patterns are determined from sequencing data ([0012]; [0037]) mapped to a reference genome (i.e. based on loci-assigned sequences) ([0098]).
McCaroll discloses b) comparing the deletion variant pattern (i.e. a gene dosage map) of the first subject (i.e. the recipient) with the deletion variant pattern of the second subject (i.e. the donor) ([0019]).
McCaroll discloses c) determining the first subject (i.e. recipient) is immuno-compatible (i.e. a transplant match) with the second subject (i.e. donor) if the first and subjects have substantially identical deletion variant patterns (e.g. at least 50%...100% identical) ([0019]).
McCaroll discloses that higher similarity between the deletion variant patterns between the first and second subject are indicative of immune-compatibility, while lower similarities are indicative of the subjects not being immune-compatible ([0019]), demonstrating the closer the correlation between the deletion variant patterns, the higher probability of immune-compatibility.
Regarding claims 58-61, McCarroll discloses a method for predicting the immuno-compatibility between a first subject that is a transplant recipient and a second subject that is a donor (Abstract; [0003]-[0004]; claim 19), wherein the method comprises the following steps:
McCarroll discloses a) determining DNA sequences of multiple genes relevant to the organ or tissue for which immune-compatibility is desired (i.e. a gene complex) by performing sequencing by hybridization on a biological sample from the first subject (the recipient) and a biological sample from the second subject (the donor) ([0012]; [0037]). McCarroll discloses the genes may be from the MHC complex ([0036]; [0045]; [0050]).
McCarroll discloses b) comparing the determined sequences to a reference genome to identify mismatch loci between the subjects and the reference genome (i.e. read mapping, which assigns the sequences to each locus of the gene complex) ([0098]).
McCarroll discloses c) determining the presence or absence of copy number deletion variants inferred by copy number for each gene (i.e. each locus) from the mapped sequences ([0012]; e.g. large deletions determined by sequencing; [0017]; [0078], e.g. deletion inferred from copy number; [0063] and FIG. 4, e.g. copy number variations determined, referred to as “Gene dosage” ). This is consistent with Applicant’s specification at pg. 21, lines 8-13 which defines a “gene dosage” to refer to a number of copies of a gene loci.
McCarroll discloses d) determining a deletion variant pattern (i.e. a gene dosage map) for the first and second subjects (i.e. the donor and recipient) ([0019]), wherein a deletion variant pattern is a compilation of the determination of the presence or absence of deletion variants in the genes of a respective biological sample and includes relative copy numbers ([0037]; [0170] and Figure 4, e.g. determined deletion genotypes include 0 or 1 copy of the gene).
McCaroll discloses e) comparing the deletion variant pattern of the first subject (i.e. the recipient) with the deletion variant pattern of the second subject (i.e. the donor) ([0019]).
Further regarding claims 58 and 60, the final wherein clause is interpreted as an intended use or result of the claimed method, which does not have patentable weight (see claim interpretation above. Regardless, it is noted that McCaroll does disclose identifying a transplant match if the deletion variant pattern of the recipient corelates with the deletion variant pattern of the recipient (see step c) of claim 57 above).
Further regarding claims 59 and 61, McCaroll discloses that higher similarity between the deletion variant patterns between the first and second subject are indicative of immune-compatibility, while lower similarities are indicative of the subjects not being immune-compatible ([0019]), and consequences of histoincompatibility include graft versus host disease (GVHD) demonstrating the closer the correlation between the deletion variant patterns, the lower the risk of developing GVHD. Furthermore, "The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Further regarding claim 61, McCaroll further discloses f) determining the first subject (i.e. recipient) is immuno-compatible with an organ of the second subject (i.e. donor) if the first and subjects have substantially identical deletion variant patterns (e.g. at least 50%...100% identical) (i.e. an organ from a transplant donor is selected for transplant to the recipient) ([0019]; claim 1).
Further regarding claims 57-61, McCaroll does not disclose the following:
Regarding claims 57-61, McCaroll does not explicitly disclose the method is computer-implemented, such that various steps are performed “using a computer”. However, the courts held that broadly providing an automatic or mechanical means to replace a manual activity which accomplished the same result is not sufficient to distinguish over the prior art. See MPEP 2144.04 III and MPEP 2114 IV.
Further regarding claims 57-61, while McCaroll does disclose determining a deletion variant pattern for the first and second subjects (considered a deletion map showing a relative copy number of each locus), McCaroll does not disclose the deletion variant pattern is a gene dosage map comprising a pictorial pattern showing copy numbers of each locus of the gene complex relative to other loci, as defined in Applicant’s specification at pg. 21, lines 13-17.
However, Jan discloses a method of determining HLA alelle-specific copy number for predicting allogenic immune response (i.e. transplant rejection) (Abstract), which comprises determining relative copy numbers for each of multiple HLA loci in an HLA gene complex and generating a pictorial representation of the relative copy numbers of the HLA loci (i.e. a gene dosage map) (Figure 2, e.g. log2ratio is relative copy number; pg. 2202, col. 1, para. 2). Jan discloses comparing the HLA allele-specific copy number profiles between two samples in the form of the pictorial representation (Figure 2A-C, e.g. see grey versus red copy number map; pg. 2200, col. 2, para. 1). Jan discloses that deletions leading to loss of heterozygosity in HLA loci contribute to matched HLA loss (pg. 2202, col. 1, para. 2-3).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified the deletion variant patterns of the recipient and donor of McCaroll to have been presented in pictorial form according to the method of Jan, discussed above, thus arriving at the inventions of claims 57-61. One of ordinary skill in the art would have been motivated to apply the known technique of presenting copy number profiles of loci in pictorial form, as shown by Jan (Figure 2) to the known method of determining deletion variant patterns of loci of McCaroll, given one of ordinary skill in the art would recognize that the visual representation of copy number profiles of Jan could be applied to the deletion profile (i.e. copy number profiles) of McCaroll. Furthermore, one of ordinary skill in the art would have recognized that the known technique of visually representing the copy number profile would have yielded the predictable result of displaying the deletion profiles between the donor and recipient of McCaroll, thus facilitating comparisons between copy number profiles of different samples, as performed in Jan (Figure 2) and McCaroll ([0019]).
Regarding the dependent claims:
Regarding claim 62, McCaroll in view of Jan, as applied to claim 58 above, disclose the gene dosage map of the gene complex for the donor and recipient. Jan discloses this gene dosage map comprises Log 2 ratios (Figure 2).
However, further regarding claim 62, McCaroll in view of Jan do not explicitly show the gene dosage maps, or log2 ratios, are generated by dividing the plurality of sequences assigned to each locus by the plurality of sequences assigned to all loci of the gene complex. However, this limitation is inherent in McCaroll in view of Jan, as evidenced by McGranahan.
Jan discloses the HLA copy numbers were determined using the tool OHHLA, citing McGranahan (pg. 2202, col. 1, para. 3). McGranahan discloses determining the log2ratios comprises binning coverage across alleles of an HLA loci (i.e. reads assigned to a given locus), and then dividing by the total number of unique reads mapped in the entire region sequenced (i.e. all loci) (pg. e2, step 4).
Regarding claim 63, McCaroll further discloses the deletion variant map comprises the presence or absence of copy number deletion variants inferred by copy number for each gene (i.e. the gene dosage for each locus is a copy number) ([0012]; e.g. large deletions determined by sequencing; [0017]; [0078], e.g. deletion inferred from copy number; [0063] and FIG. 4, e.g. copy number variations determined, referred to as “Gene dosage” ).
Regarding claims 64-65, and 67, the claims fail to further limit the subject matter of claims 57, 58, and 63, from which they depend, and thus are rejected for the same reasons discussed above for claims 57-58 and 63.
Regarding claims 66 and 68, McCaroll discloses the gene complex may be an HLA complex ([0036]; [0042]; [0045]).
Regarding claim 69, McCaroll further discloses the assigning is based on comparing the determined sequences (i.e. the entire sequence of each locus) to a reference genome ([0098]).
Regarding claim 70, McCaroll does not explicitly disclose the assigning is performed using a computer program. However, the courts held that broadly providing an automatic or mechanical means to replace a manual activity which accomplished the same result is not sufficient to distinguish over the prior art. See MPEP 2144.04 III and MPEP 2114 IV.
Regarding claims 86-88, the limitations only serve to define the process in which the loci-assigned sequences of claim 57 were previously generated. The loci assigned sequences of McCaroll, discussed above for claim 57, are the same product as those in the claims, and thus discloses the limitations of claims 86-88, even if the assigned loci of the claims were determined by a different process. See MPEP 2113 I.
Regardless, regarding claims 86-87, McCaroll discloses nucleic acid from the first and second subject is extracted from a blood sample (claims 1 and 4-5; [0032]; [0177], e.g. DNA isolated).
Regarding claim 91, McCaroll does not explicitly disclose the sequences are generated in computer-readable form. However, the courts held that broadly providing an automatic or mechanical means to replace a manual activity which accomplished the same result is not sufficient to distinguish over the prior art. See MPEP 2144.04 III and MPEP 2114 IV.
Therefore, the invention is prima facie obvious.
Claims 71-85 and 89-90 are rejected under 35 U.S.C. 103 as being unpatentable over McCaroll in view of Jan, as applied to claims 58 and 70 above, and further in view of Gnirke (2009).
Cited reference: Gnirke et al., Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing, 2009, Nature Biotechnology, 27(2), pg. 182-189.
Regarding claims 71-85 and 89-90, McCaroll in view of Jan disclose the method of claims 58 and 70 as applied above.
Further regarding claim 71, McCaroll in view of Jan does not disclose the computer program used to assign the plurality of sequences is a sequencing editing and alignment program.
However, Gnirke discloses a method for performing sequencing and determining base calls (Abstract; pg. 188, col. 1, para. 4 to col. 2, para. 1), which comprises computationally aligning reads to the human genome and excluding bases from the aligned sequences that failed a signal clarity filter (i.e. sequence editing) using an ARACHNE genome assembly suite (pg. 188, col. 1, para. 4 to col. 2, para. 1).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified the method of McCaroll in view of Jan, as applied to claim 70 above, to have assigned the plurality of sequences using a sequencing editing and alignment program, as shown by Gnirke above. One of ordinary skill in the art would have been motivated to combine the methods of McCaroll in view of Gnirke in order to provide high-confidence base calls excluding low quality bases, as shown by Gnirke (pg. 188, col. 2, para. 1), thus facilitating the accurate identification of variants in McCaroll. This modification would have had a reasonable expectation of success given McCaroll discloses mapping sequence reads to a reference genome ([0098]), such that the alignment and editing program of Gnirke is applicable to the sequencing data of McCaroll.
Further regarding claims 72, 76, 79-85, and 89-90, McCaroll in view of Jan, as applied to claim 58 above, do not disclose the following limitations:
Regarding claim 72 and 89-90, while McCaroll discloses identifying the deletion variants comprises performing DNA sequencing on a preferred subset of the whole genome, including DNA sequences encoding protein sequences known to be presented by the MHC (i.e. HLA genes) ([0012]; [0045]), McCaroll in view of Jan, as applied to claim 58 above, does not disclose the sequencing comprises performing hybrid-capture next generation sequencing (claims 89-90) by: a) contacting a nucleic acid sample from the one or more transplant donors and the recipient with oligonucleotide probes, wherein the oligonucleotide probes hybridize to gene target sequences in the nucleic acid sample; b) enriching a nucleic acid by hybridizing the nucleic acid to one or more oligonucleotide probes; c) separating nucleic acid hybridized to the one or more oligonucleotide probes from nucleic acid not hybridized to the one or more oligonucleotide probes; and d) sequencing the enriched nucleic acid to identify one or more gene alleles; wherein the gene target sequences are in a non-coding region of the gene (claim 72).
Regarding claim 76, McCaroll in view of Jan, as applied to claim 58 above, does not disclose amplifying nucleic acid bound to the one or more oligonucleotide probes.
Regarding claims 79-82, McCaroll in view of Jan, as applied to claim 58 above, does not disclose the oligonucleotide probes comprise a biotin or streptavidin capture tag and contacting the capture tag with a biotin or streptavidin binding agent.
Regarding claim 83¸ McCaroll in view of Jan, as applied to claim 58 above, does not disclose the nucleic acid sample from the transplant donor and recipient contacted with the oligonucleotide probes is single stranded nucleic acid.
Regarding claims 84-85, McCaroll in view of Jan, as applied to claim 58 above, does not disclose fragmenting the nucleic acid sample before or after being contacted with the oligonucleotide probes, wherein the fragments have an average length of over about 100 bp.
However, Gnirke discloses the above method of performing next-generation hybrid capture sequencing (Abstract) encompassed by claims 72, 76, and 79-85 as follows.
Gnirke discloses fragmenting genomic DNA prior to contacted by oligonucleotide probes to 200-350 bp fragments with an average size of 250 bp (i.e. an average length of over 100 bp) (Figure 1; pg. 183, col. 2, para. 3). Gnirke further discloses hybridizing (i.e. contacting) the single-stranded fragmented DNA to biotinylated RNA bait (i.e. oligonucleotide probes comprising a biotin capture tag) (pg. 183, col. 2, para. 3; Figure 1, e.g. single stranded fragment bound to RNA bait), capturing the DNA-RNA bait complex is on streptavidin-coated magnetic beads (Figure 1; pg. 183, col. 1, para. 2 to col. 2, para. 1), and then separating and enriching the bead-captured DNA via elution (Figure 1; pg. 188, col. 1, para. 2). Following elution, Gnirke discloses performing PCR amplification on the captured DNA and then performing next-generation sequencing the amplified fragments (Figure 1; pg. 183, col. 2, para. 3; pg. 188, col. 2, para. 2; pg. 186, col. 2, para. 5).
Gnirke further discloses that the simple pull-down technique with streptavidin-coated magnetic beads, discussed above, does not require any customized equipment and works well in combination with any sequencing platform, thus allowing extensive sequencing of targeted loci in genomes (pg. 186, col. 2, para. 5 to pg. 187, col. 1, para. 1; pg. 187, col. 2, para. 2).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified the targeted sequencing method of McCaroll to have utilized the hybrid-capture next-generation sequencing method of Gnirke, discussed above, and thus arriving at the inventions of claims 72, 76, and 79-85. One of ordinary skill in the art would have bene motivated to combine the methods of McCaroll and Gnirke to facilitate extensive sequencing of targeted loci without the need for any customized equipment or specific sequencing platforms, as shown by Gnirke (pg. 186, col. 2, para. 5 to pg. 187, col. 1, para. 1; pg. 187, col. 2, para. 2). This modification would have had a reasonable expectation of success given McCaroll discusses only sequencing a preferred subset of the genome, and thus the hybrid-capture method of sequencing targeted regions of Gnirke could be used to generate the sequencing data of preferred regions in McCaroll.
Regarding claims 73-75 and 77-78, McCaroll in view of Jan and Gnirke disclose the method of claim 72, as applied above.
Further regarding claims 73-75¸ McCaroll discloses the gene complex may be an HLA complex ([0036]; [0042]). It is further noted claim 74 fails to further limit the subject matter of claim 72, from which it depends, and thus claim 74 is rejected for the same reasons as claim 72.
Further regarding claims 77-78, McCaroll discloses identifying the deletion variants comprises performing DNA sequencing on a preferred subset of the whole genome, including DNA sequences encoding protein sequences known to be presented by the MHC (i.e. an HLA gene exon and entire HLA gene complex) ([0012]; [0045]). McCaroll further discloses the preferred subset may be DNA sequences encoding proteins known to be expressed in a particular organ type of interest (i.e. a gene exon or entire gene complex pertaining to transplantation) ([0045]). In another embodiment, McCaroll discloses the preferred subset is all DNA sequences encoding proteins ([0045]), which necessarily includes an entire HLA gene complex.
Therefore, the invention is prima facie obvious.
Claim 92 is rejected under 35 U.S.C. 103 as being unpatentable over McCaroll in view of Jan, as applied to claim 91 above, and further in view of Roy (2016).
Cited reference: Roy et al., Next-Generation Sequencing Informatics: Challenges and Strategies for Implementation in a Clinical Environment, 2016, Arch Pathol Lab Med, 140, pg. 958-975.
Regarding claim 92, McCaroll in view of Jan disclose the method of claim 91 as applied above.
Further regarding claim 92, McCaroll in view of Jan, as applied to claim 91 above, does not disclose the sequences are generated in a FASTQ format.
However, Roy overviews informatics solutions to next-generation sequencing data (Abstract), and discloses that sequences reads generated during sequencing are stored in one of several file formats, including FASTQ, XSEQ, unaligned BAM, or FASTA (pg. 960, col. 1, para. 1-2). Roy discloses FASTQ files are smaller than raw data files and are platform-independent entry points into common bioinformatics tool, thus offering a much higher utility for the incurred cost of storage (pg. 969, col. 1, para. 2).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified the computer-readable sequences of McCaroll in view of Jan, to have been stored in a FASTQ file format, as shown by Roy above. One of ordinary skill in the art would have been motivated to combine the methods of McCaroll in view of Jan and Roy in order to provide sequencing data in a platform-independent format that is smaller than raw data files, thus offering higher utility per storage cost, as shown by Roy (pg. 969, col. 1, para. 2). This modification would have had a reasonable expectation of success because Roy discloses FASTQ formats are used to store sequence reads generated during sequencing (pg. 960, col. 1, para. 1-2), and thus the sequencing data of McCaroll in view of Roy could be stored in a FASTQ format.
Therefore, the invention is prima facie obvious
Conclusion
No claims are allowed.
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/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685
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