DETAILED ACTION
This application is being examined under AIA first-to-file provisions.
Status of claims
Canceled:
7-20
Pending:
1-6
Withdrawn:
none; however, the 1/23/2024 restriction requirement remains in effect
Examined:
1-6
Independent:
1
Allowable:
none
Rejections applied
Abbreviations
x
112/b Indefiniteness
PHOSITA
"a Person Having Ordinary Skill In The Art before the effective filing date of the claimed invention"
112/b "Means for"
BRI
Broadest Reasonable Interpretation
112/a Enablement,
Written description
CRM
"Computer-Readable Media" and equivalent language
112 Other
IDS
Information Disclosure Statement
x
102, 103
JE
Judicial Exception
x
101 JE(s)
112/a
35 USC 112(a) and similarly for 112/b, etc.
101 Other
N:N
page:line
Double Patenting
MM/DD/YYYY
date format
Priority
As detailed on the 12/5/2023 filing receipt, this application was filed 11/20/2023, and there is no claim to earlier priority.
Withdrawal / revision of objections and/or rejections
In view of the amendment and remarks:
The previous claim objections are withdrawn, except as noted below.
The previous 112/b rejections are withdrawn, except as noted below, and new rejections are applied.
Rejections and/or objections not maintained from previous office actions are withdrawn. The following rejections and/or objections are either maintained or newly applied. They constitute the complete set applied to the instant application.
Claim objections
Claim 1 is objected to because of the following informalities. Appropriate correction is required. In each objection the claims are definite with respect to the issues cited here because interpretation would have been sufficiently clear to PHOSITA, but nonetheless the claims are objected to for consistency among the claims or as otherwise indicated. With regard to any suggested amendment below to overcome an objection, in the subsequent examination it is assumed that each amendment is made. However, equivalent amendments also would be acceptable. Any amendments in response to the following objections should be applied throughout the claims, as appropriate.
The following issues are objected to:
Claim
Recitation
Comment
1
generating...
noncase relationship
In most instances, the claim recites "non-case,"
as opposed to "noncase." Thus, this instance should read "non-case."
Claim rejections - 112/b
The following is a quotation of 35 USC 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 1-6 are rejected under 112/b, as indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention. Claims depending from rejected claims are rejected similarly, unless otherwise noted, and any amendments in response to the following rejections should be applied throughout the claims, as appropriate. With regard to any suggested amendment below, for claim interpretation during the present examination it is assumed that each amendment suggested here is made. However equivalent amendments also would be acceptable.
The following issues cause the respective claims to be rejected under 112/b as indefinite:
Claim
Recitation
Comment (suggestions in bold)
1
conventional
The recited "conventional" is a term of relative or vague degree or form of association, neither defined in the specification (p. 8, Table 1) nor having a well-known and sufficiently particular definition in the art and in the instant context. In Table 1, the distinction between conventional and not conventional is unclear such that it is unclear what requirement the term "conventional" creates in the claim. (MPEP 2173.05(b) pertains.)
If what is intended is a biomarker which does not describe or relate to a relationship between two other biomarkers then such negative limitation may be recited in the claim. Alternatively, it may suffice simply to delete the term "conventional" if the subsequent recitation already establishes the intended term scope.
1
applying a mathematical function over a relationship of the case covariation and non-case covariation to generate the at least one relational biomarker.
It is unclear what is required by the recited "applying a mathematical function over a relationship." Typically, a math function takes as input values, e.g. integers, real numbers, etc. It is unclear what is required by the implied math function taking as input a "relationship."
If what is intended is that a math function is created which models or otherwise represents a relationship of the case covariation and non-case covariation and generates as output the at least one relational biomarker, then (i) this may be clarified and (ii) support should be identified for any amendment.
This rejection is maintained.
2
...the relational biomarkers
In claim 2, the recitation requires but lacks clear antecedent, there being, for example, no preceding recitation of "biomarkers" plural, let alone "relational biomarkers."
2-3
the relationships of case covariation and non-case covariation of additional biomarkers from biological material from each of the plurality of case and non-case samples, respectively
In claim 2, the recitation requires but lacks clear antecedent, there being, for example, no prior recitation of "relationships" plural. Also, the recited "of case covariation and non-case covariation of additional biomarkers from biological material from each of the plurality of case" also requires but lacks antecedent.
Claim 3 is rejected similarly.
2-3
...of additional biomarkers...
In claim 2, the relationship is unclear between this new instantiation of "additional biomarkers" vs. the "at least one additional conventional biomarker" of the second "defining" step of claim 1.
Claim 3 is rejected similarly.
3, 6
at least one additional biological material
The relationship is unclear between this instance and that of claim 1. It may help to enumerate the instances as "first," "second," etc.
Claim 6 is rejected similarly.
4
; ... ,
The use of semi-colons and commas separating list elements within the same list renders the claim indefinite. The relationships are unclear among the list elements. It is unclear how to interpret the recited "any combinations," e.g. combinations of semi-colon-separated list elements, comma-separated list elements, and/or singular vs. plural instances of list elements.
5
..., or a mathematical transformation of the variable
The relationship is unclear between this element and the rest of the claim. First, in a recitation such as "X or Y", there should be no comma between "X" and "Y", e.g. not "X, or Y." It is unclear what is the first element in the recited "or" clause, e.g. "...comprise ..., or..." vs. "...representing ..., or...", etc.
6
an expected accuracy of the discriminator for classifying the unknown biological sample as a case or non-case sample for the disease or disorder or each additional disease or disorder
The relationships are unclear between the recited instances of "discriminator" and the instances of "disease or disorder." This is at least because the first instance of "a discriminator" in claim 3 relates to "the disease or disorder" of claim 1, while the claim 3 "ensemble of discriminators" relates to "additional diseases or disorders." However, claim 6 recites only "the discriminator" but in relation to both "the disease or disorder" and "each additional disease or disorder." Possibly claim 6 also should make clear any relationship to the ensemble.
Claim rejections - 102
In the event the determination of the status of the application as subject to AIA 35 USC 102 and 103 is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Response to arguments regarding Claim Rejections - 35 USC 102
Applicant states (emphasis removed/added, applicant remarks: p. 5):
...comprising applying a mathematical function of the relationship between the plurality of conventional biomarkers, as recited in Claim 1...
It cannot be agreed that claim 1 includes the asserted recitation.
Applicant states (emphasis removed/added, applicant remarks: p. 6):
...Zethelius uses a Cox proportional hazards model, which is a linear regression model. The linear regression model aggregates the same model with multiple inputs of biomarkers. However, each relationship between each of the biomarkers are not taken into consideration in this linear regression model...
Essentially, Zethelius teaches a linear model, where outcome is dependent on a model performed on an input. Additional inputs may be applied to the model, but the model does not explore relationships between each input. A relationship between the outcome and the inputs is explored through the linear model, but the outcome does not depend on the relationship between each input.
...the proposed invention applies a mathematical function over a relationship between covariance of biomarkers
...
The proposed invention... claims a mathematically distinct operation, one that is beyond adding more inputs into a single linear model. Instead, the proposed invention examines an additional layer of mathematical relationship between each input.
...
By contrast, the proposed invention model is akin to...
Regarding the first two remarks paragraphs quoted above as paraphrasing and summarizing Zethelius, the relevance of these remarks is unclear at least because the relationship is unclear between the remarks and the precise claim recitation. For example, the claim does not recite "between," and that portion of the claim recitation causes the claim to be indefinite as described in an above 112b rejection.
The term "modeling" is recited, but the term "model" is not, such that it is at least unclear what is the asserted "model."
Furthermore, the following assertions in the remarks are unclear: "beyond adding more inputs into a single linear model" and "an additional layer of mathematical relationship between each input." This is at least because the relationship is unclear between the claims and the remarks.
The following remarks assertion is unclear: "the proposed invention model is akin to..."
Claims 1-6
Claims 1-6 are rejected under 35 USC 102(a)(1) as anticipated by Zethelius (as cited on the 1/30/2025 "Notice of References Cited" form 892).
Regarding claim 1, the recited relating patterns from biological materials, and associated recitations are taught as at least Zethelius' "Multiple Biomarkers" (Zethelius: title and entire document).
The recited material types read on at least one of Zethelius' specific "biomarkers" (Zethelius: §"METHODS;" and entire document).
The recited case and noncase relationships read on Zethelius' "...both... the whole cohort... and in the group... who did not have cardiovascular disease..." (Zethelius: §"RESULTS;" and entire document).
The recited applying a mathematical function over a relationship of the plurality of biomarkers to generate the at least one relational biomarker reads on Zethelius' "...adding multiple biomarkers from different disease pathways for predicting the risk of death from cardiovascular causes..." (Zethelius: §"BACKGROUND;" and entire document) and "...biomarkers were incorporated into a model..." (Zethelius: §"RESULTS;" and entire document), the recited relational biomarker reads on Zethelius' model combining multiple biomarkers.
The instant specification discloses at [4] (emphasis added):
"A relational biomarker is a mathematical function whose domain is two or more variables that represent patterns of or on biological materials such as methylation levels on DNA, DNA fragmentome signatures, RNA transcription levels, RNA splicing isoforms, DNA copy number variants, protein abundance and modification, metabolite profiles, and the like. Said differently, a relational biomarker is a mathematical function that represents the covarying behavior of two or more conventional biomarkers."
The recited "relational biomarker" reads on at least Zethelius' "model," "prediction," "C statistic" and "...four biomarkers were incorporated into a model with established risk factors..." (Zethelius: §"BACKGROUND;" §"RESULTS;" and entire document).
Regarding claim 2, the recited ensemble of relational biomarkers reads on Zethelius' "Established risk factors plus all biomarkers" (Zethelius: Table 3, associated text; and entire document) as well as Zethelius' model (Zethelius: §"BACKGROUND;" §"RESULTS;" and entire document).
Regarding claim 3, the recited ensemble of discriminators for additional diseases reads on Zethelius' "C Statistic for Death from Cardiovascular Causes" vs. "C Statistic for Death from All Causes" (Zethelius: Table 3, associated text; and entire document).
Regarding claim 4, the recited types of biological material read on Zethelius' "Biomarkers" (Zethelius: Table 3, associated text; and entire document).
Regarding claim 5, the recited patterns read on Zethelius' "C Statistic" (Zethelius: Table 3, associated text; and entire document).
Regarding claim 6, the recited maximization of accuracy reads on Zethelius' "...the C statistic increased significantly for the prediction of death from cardiovascular causes when all the biomarkers we measured were incorporated..." (Zethelius: §"DISCRIMINATION;" and entire document).
Claim rejections - 101
35 USC 101 reads:
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.
For each rejection below, dependent claims are rejected similarly as not remedying the rejection, unless otherwise noted.
Response to arguments regarding Claim Rejections - 35 USC 101 -- Abstract idea
Applicant states (original emphasis removed, bold emphasis added, applicant remarks: p. 7):
This is an improved process that is not described, referenced, taught, or within the scope of the cited reference. This is an improvement that accomplishes what was no accomplished before, namely identifying biological samples as case or non-case by examining relationships between biomarkers (which would not be able to demonstrate covariance in a linear model). Because adding biomarkers in a linear model still relies on the biomarkers having some level of relationship to the outcome, any biomarkers without any relationship to the outcome would not be considered. By contrast, the proposed invention may identify such relationship by modeling relationship between these unconsidered biomarkers, thereby enabling clinicians to classify biological samples in a previously non-existent manner.
Applicant makes an argument under MPEP 2106, Step 2A, 2nd prong, 1st consideration regarding an improvement over the previous state of the technology field.
As discussed in the response to remarks regarding 102, it is not clear that the cited art does not teach embodiments within the scope of the claims. Without a difference, there can be no improvement.
It is acknowledged that the asserted improvement is accomplishing what is asserted as not accomplished before, i.e. identifying biological samples as case or non-case by examining relationships between biomarkers. However, Zethelius' model is understood as itself being a form of relational biomarker incorporating relationships among other non-relational biomarkers. Therefore, it is not yet clear that the improvement can be simply what was not accomplished before.
It may help to overcome the 112/b rejections, clarifying the claims and possibly distinguishing them from the cited art as an example of the previous state of the technology field.
Judicial exceptions (JE) to 101 patentability
Claims 1-6 are rejected under 35 USC 101 because the claimed inventions are not directed to patent eligible subject matter. After consideration of relevant factors with respect to each claim as a whole, each claim is directed to one or more JEs (i.e. an abstract idea, a natural phenomenon, a law of nature and/or a product of nature), as identified below. Any elements or combination of elements beyond the JE(s) (i.e. "additional elements") are conventional and do not constitute significantly more than the JE(s). Thus, no claim includes additional elements amounting to significantly more than the JE(s), as explained below.
In Alice, citing Mayo and Bilski, two Mayo/Alice questions determine eligibility under 101: First, is a claim directed to a JE? And second, if so, does the claim recite significantly more than the JE?
MPEP 2106 organizes JE analysis into Steps 1, 2A (1st & 2nd prongs) and 2B as follows below.
MPEP 2106 and the following USPTO website provide further explanation and case law citations: www.uspto.gov/patent/laws-and-regulations/examination-policy/examination-guidance-and-training-materials.
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter? -- MPEP 2106.I and 2106.03
[Step 1: claims 1-6: YES]
Step 2A, 1st prong: Do the claims recite a judicially recognized exception, i.e. a law of nature, a natural phenomenon, or an abstract idea? -- abstract idea -- MPEP 2106.I and 2106.04
Preliminarily, in a 1st prong of Step 2A, elements of independent claim 1 are interpreted as directed to the abstract idea of relating biological sample data to disease state including the JE elements of "defining..." (two instances), "...determining..." (two instances), "generating..." (two instances) and "applying...," each of which, including all recitation within each listed element, in at least some embodiments within a BRI, involves only manipulation of data. While manipulation of data is not per se directed to an abstract idea, in this instance the above-identified elements are directed to the abstract ideas identified below.
BRIs of the claims are analogous to an abstract idea in the form of at least a mental process, at least equivalent to a computer-implemented process, including obtaining and comparing intangible data (e.g. Cybersource, Synopsys and Electric Power Group). In a BRI, it is not clear that the claim embodiments are limited so as to require complexity precluding analogy to a mental process.
BRIs of the claims also are analogous to an abstract idea in the form of a mathematical concept, including mathematical relationships and calculations, as found in the following case law, as cited and discussed above: collecting information, analyzing it, and displaying certain results of the collection and analysis (Electric Power Group) and/or obtaining and comparing intangible data (e.g. Cybersource, Ambry and Myriad CAFC) and/or execution of an algorithm to implement mathematical relationships and/or formulas, including image processing (e.g. TLI, Digitech, Benson, Flook, Diehr, FuzzySharp, In re Grams and In re Abele all as cited in MPEP 2106).
Instant examples of math concepts include the recited "mathematical function," as well as relationships inherent in recitations as the only supported embodiments.
The preceding case law examples are cited for the basic form of their identified abstract ideas, and analogy to these example abstract ideas need not be within the same technology field, 101 analysis generally being assumed to be neutral with respect to technology field.
As in Alice (at 306, as cited in the MPEP above) and Bilski (as cited in Alice, id), an abstract idea may comprise multiple abstract elements or steps (i.e. from Alice: "a series of steps" at 306) and need not be a single equation, relationship or principle.
It is not clear that the identified elements must represent other than an abstract idea according to any relevant analysis or case law.
[Step 2A, 1st prong, abstract idea: claim 1: YES]
Step 2A, 1st prong: Do the claims recite a judicially recognized exception, i.e. a law of nature, a natural phenomenon, or an abstract idea? -- law of nature -- MPEP 2106.I and 2106.04
Preliminarily, at this 1st step of the analysis, elements of independent claim 3 are directed to a law relating sample data to diagnosis, including the JE element of "classifies an unknown biological sample as a case or noncase sample."
A BRI of the instant claims is analogous to a law of nature as found, for example, in Mayo (as cited in the MPEP above). It is not clear than any improvement argument clearly on the record causes a claim not to be directed to a JE for all embodiments within the scope of the claim. It is not clear that the above identified law of nature including the identified elements, taken together and within a BRI, must in all embodiments represent other than a law of nature according to any relevant analysis or case law. Therefore, in answer to the 1st Mayo/Alice question, the above elements are directed to a law of nature.
Step 2A, 2nd prong: If the claims recite a judicial exception under the 1st prong, then is the judicial exception integrated into a practical application? -- MPEP 2106.I and 2106.04(d)
MPEP 2106.04(d).I lists the following example considerations for evaluating whether a judicial exception is integrated into a practical application:
An improvement in the functioning of a computer or an improvement to other technology or another technical field, as discussed in MPEP §§ 2106.04(d)(1) and 2106.05(a);
Applying or using a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition, as discussed in MPEP § 2106.04(d)(2);
Implementing a judicial exception with, or using a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim, as discussed in MPEP § 2106.05(b);
Effecting a transformation or reduction of a particular article to a different state or thing, as discussed in MPEP § 2106.05(c); and
Applying or using the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception, as discussed in MPEP § 2106.05(e).
In Step 2A, 1st prong above, claim steps and/or elements were identified as part of one or more judicial exceptions (JEs).
In Step 2B below, any remaining steps and/or elements are therefore in addition to the identified JE(s). Any such additional steps and additional elements are further discussed in Step 2B.
Here in Step 2A, 2nd prong, no additional step or element clearly demonstrates integration of the JE(s) into a practical application.
At this point in examination it is not yet the case that any of the Step 2A, 2nd prong considerations enumerated above clearly demonstrates integration of the identified JE(s) into a practical application. Referring to the considerations above, none of 1. an improvement, 2. treatment, 3. a particular machine or 4. a transformation is clear in the record.
For example, regarding the first consideration at MPEP 2106.04(d)(1), the record does not yet clearly disclose an explanation of improvement over the previous state of the technology field. The claims do not yet clearly result in such an improvement (e.g. specification: [3]). The above response to Applicant's remarks also pertains
[Step 2A, 2nd prong: claim 1: NO]
Step 2B: Do the claims recite a non-conventional arrangement of additional elements in addition to the identified JEs? -- MPEP 2106.I and 2106.05
Addressing the second Mayo/Alice question, all elements of claim 1 are part of one or more identified JEs (as described above).
It is emphasized that, outside of an improvement argument, analysis of what is conventional generally pertains to the above-identified additional elements and not to elements identified as part of a JE.
Suggestions regarding advancing examination by improvement argument versus non-conventional additional element argument are provided in the bullets at the end of this rejection.
[Step 2B: claim 1: NO]
Summary and conclusion regarding claims 1 and 3
Summing up the above analysis of claims 1 and 3, each viewed as a whole and considering all elements individually and in combination, no claim recites limitations that transform the claim, finally interpreted as directed to the identified JE(s), into patent eligible subject matter, and it is not clear that any claim is sufficiently analogous to controlling case law identifying an example of an eligible claim.
Remaining claims
Claims 2 and 4-6 add elements which also are part of the identified JEs for the same reasons described above regarding the independent claims and therefore do not provide the something significantly more necessary to satisfy 101.
None of the dependent claim elements provides the something significantly more than the identified JE(s) necessary to satisfy 101.
Citations to art
In the above citations to documents in the art, rejections refer to the portions of each document cited as example portions as well as to the entirety of each document, unless otherwise noted in the situation of lengthy, multi-subject documents. Other passages not specifically cited within a document may apply as well.
Conclusion
No claim is allowed. Applicant's amendments necessitated the new grounds for rejection in this action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Inquiries
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The examiner for this Office action, G. Steven Vanni, may be contacted at:
(571) 272-3855 Tu-F 8-7 (ET). If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Larry D. Riggs, II, may be reached at (571) 270-3062.
/G. STEVEN VANNI/Primary patents examiner, Art Unit 1686